| 1 | Hum. Mol. Genet. 2002 Sep 11: 2243-9 |
|---|---|
| PMID | 12217952 |
| Title | PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. |
| Abstract | The increased prevalence of schizophrenia among patients with the 22q11 interstitial deletion associated with DiGeorge syndrome has suggested the existence of a susceptibility gene for schizophrenia within the DiGeorge syndrome chromosomal region (DGCR) on 22q11. Screening for genomic rearrangements of 23 genes within or at the boundaries of the DGCR in 63 unrelated schizophrenic patients and 68 unaffected controls, using quantitative multiplex PCR of short fluorescent fragments (QMPSF), led us to identify, in a family including two schizophrenic subjects, a heterozygous deletion of the entire PRODH gene encoding proline dehydrogenase. This deletion was associated with hyperprolinemia in the schizophrenic patients. In addition, two heterozygous PRODH missense mutations (L441P and L289M), detected in 3 of 63 schizophrenic patients but in none among 68 controls, were also associated with increased plasma proline levels. Segregation analysis within the two families harboring respectively the PRODH deletion and the L441P mutation showed that the presence of a second PRODH nucleotide variation resulted in higher levels of prolinemia. In two unrelated patients suffering from severe type I hyperprolinemia with neurological manifestations, we identified a homozygous L441P PRODH mutation, associated with a heterozygous R453C substitution in one patient. These observations demonstrate that type I hyperprolinemia is present in a subset of schizophrenic patients, and suggest that the genetic determinism of type I hyperprolinemia is complex, the severity of hyperprolinemia depending on the nature and number of hits affecting the PRODH locus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 2 | Hum. Mol. Genet. 2002 Sep 11: 2243-9 |
| PMID | 12217952 |
| Title | PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. |
| Abstract | The increased prevalence of schizophrenia among patients with the 22q11 interstitial deletion associated with DiGeorge syndrome has suggested the existence of a susceptibility gene for schizophrenia within the DiGeorge syndrome chromosomal region (DGCR) on 22q11. Screening for genomic rearrangements of 23 genes within or at the boundaries of the DGCR in 63 unrelated schizophrenic patients and 68 unaffected controls, using quantitative multiplex PCR of short fluorescent fragments (QMPSF), led us to identify, in a family including two schizophrenic subjects, a heterozygous deletion of the entire PRODH gene encoding proline dehydrogenase. This deletion was associated with hyperprolinemia in the schizophrenic patients. In addition, two heterozygous PRODH missense mutations (L441P and L289M), detected in 3 of 63 schizophrenic patients but in none among 68 controls, were also associated with increased plasma proline levels. Segregation analysis within the two families harboring respectively the PRODH deletion and the L441P mutation showed that the presence of a second PRODH nucleotide variation resulted in higher levels of prolinemia. In two unrelated patients suffering from severe type I hyperprolinemia with neurological manifestations, we identified a homozygous L441P PRODH mutation, associated with a heterozygous R453C substitution in one patient. These observations demonstrate that type I hyperprolinemia is present in a subset of schizophrenic patients, and suggest that the genetic determinism of type I hyperprolinemia is complex, the severity of hyperprolinemia depending on the nature and number of hits affecting the PRODH locus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 3 | Mol. Psychiatry 2003 Jul 8: 644-5 |
| PMID | 12874599 |
| Title | Association between PRODH and schizophrenia is not confirmed. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 4 | Neurosci. Lett. 2003 Mar 338: 252-4 |
| PMID | 12581843 |
| Title | A family-based association study of T1945C polymorphism in the proline dehydrogenase gene and schizophrenia in the Chinese population. |
| Abstract | Previous studies have reported genetic linkage evidence for a candidate gene of schizophrenia on chromosome 22q11 but no genes in this region have been really confirmed to be involved in the etiology of schizophrenia so far. Very recently, the proline dehydrogenase gene (PRODH), located in the most centromeric part of the 22q11 microdeletion region, has been reported to be strongly associated with schizophrenia from three sets of independent samples and the most significant evidence for association was derived from a single nucleotide polymorphism-PRODH*1945(T/C). We genotyped this polymorphism in 166 Chinese family trios with schizophrenia from East China. No evidence for preferential transmission of the PRODH*1945 alleles from parents to affected offsprings was found using either Transmission Disequilibrium Test (P=0.4) or Haplotype-based Haplotype Relative Risk analysis (P=0.35). Our results suggest that the 1945(T/C) polymorphism of the proline dehydrogenase gene is unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 5 | Nat. Struct. Biol. 2003 Feb 10: 109-14 |
| PMID | 12514740 |
| Title | Structure of the proline dehydrogenase domain of the multifunctional PutA flavoprotein. |
| Abstract | The PutA flavoprotein from Escherichia coli plays multiple roles in proline catabolism by functioning as a membrane-associated bi-functional enzyme and a transcriptional repressor of proline utilization genes. The human homolog of the PutA proline dehydrogenase (PRODH) domain is critical in p53-mediated apoptosis and schizophrenia. Here we report the crystal structure of a 669-residue truncated form of PutA that shows both PRODH and DNA-binding activities, representing the first structure of a PutA protein and a PRODH enzyme from any organism. The structure is a domain-swapped dimer with each subunit comprising three domains: a helical dimerization arm, a 120-residue domain containing a three-helix bundle similar to that in the helix-turn-helix superfamily of DNA-binding proteins and a beta/alpha-barrel PRODH domain with a bound lactate inhibitor. Analysis of the structure provides insight into the mechanism of proline oxidation to pyrroline-5-carboxylate, and functional studies of a mutant protein suggest that the DNA-binding domain is located within the N-terminal 261 residues of E. coli PutA. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 6 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jul 120B: 42-6 |
| PMID | 12815738 |
| Title | Detailed analysis of PRODH and PsPRODH reveals no association with schizophrenia. |
| Abstract | People with deletion of the chromosome 22q11 region associated with velo cardio-facial syndrome (VCFS) have a remarkably high risk of developing schizophrenia. Recently, the gene proline dehydrogenase (PRODH) which maps to 22q11 and is also an excellent functional candidate gene for psychosis, has been reported to show genetic association with schizophrenia. We have screened all the exons and adjacent intronic sequences of PRODH for the presence of sequence variation in 14 DSM IV schizophrenic subjects. Similarly, we also screened all putative exons of a sequence that is similar to proline dehydrogenase (PsPRODH) and which also maps within the deleted region. A total of nine single nucleotide polymorphisms (SNPs) were identified in PRODH, eight of which were exonic, while in PsPRODH, five SNPs were identified, one of which was in a putative exon. All samples were tested for association in a pooled sample of 368 DSM IV diagnosed schizophrenic subjects and 368 matched controls. None of the variants identified in PRODH gave even modest evidence for allelic association (P < 0.1). In PsPRODH, two variants (-3864G > A and 226G > A) gave P values < 0.1. These were individually genotyped in the same subjects that had been used to construct the pools. Although a trend for association was confirmed, neither showed evidence for association at the P PRODH or PsPRODH contribute to the aetiology of schizophrenia, and that the putative schizophrenia susceptibility gene in 22q11 remains unknown. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 7 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jul 120B: 42-6 |
| PMID | 12815738 |
| Title | Detailed analysis of PRODH and PsPRODH reveals no association with schizophrenia. |
| Abstract | People with deletion of the chromosome 22q11 region associated with velo cardio-facial syndrome (VCFS) have a remarkably high risk of developing schizophrenia. Recently, the gene proline dehydrogenase (PRODH) which maps to 22q11 and is also an excellent functional candidate gene for psychosis, has been reported to show genetic association with schizophrenia. We have screened all the exons and adjacent intronic sequences of PRODH for the presence of sequence variation in 14 DSM IV schizophrenic subjects. Similarly, we also screened all putative exons of a sequence that is similar to proline dehydrogenase (PsPRODH) and which also maps within the deleted region. A total of nine single nucleotide polymorphisms (SNPs) were identified in PRODH, eight of which were exonic, while in PsPRODH, five SNPs were identified, one of which was in a putative exon. All samples were tested for association in a pooled sample of 368 DSM IV diagnosed schizophrenic subjects and 368 matched controls. None of the variants identified in PRODH gave even modest evidence for allelic association (P < 0.1). In PsPRODH, two variants (-3864G > A and 226G > A) gave P values < 0.1. These were individually genotyped in the same subjects that had been used to construct the pools. Although a trend for association was confirmed, neither showed evidence for association at the P PRODH or PsPRODH contribute to the aetiology of schizophrenia, and that the putative schizophrenia susceptibility gene in 22q11 remains unknown. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 8 | Schizophr. Res. 2004 Mar 67: 111-3 |
| PMID | 14741331 |
| Title | Failure to find association between PRODH deletion and schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 9 | Hum. Mutat. 2004 Jul 24: 35-42 |
| PMID | 15221787 |
| Title | Functional analysis of polymorphisms in the promoter regions of genes on 22q11. |
| Abstract | Segmental aneusomy, which includes chromosome 22 deletion syndrome (del(22)(q11.2q11.2)), has been associated with DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face (CAF) syndrome, cat-eye syndrome (CES), der(22) syndrome, and duplication of the del(22)(q11.2q11.2) syndrome's typically deleted region. Adults with del(22)(q11.2q11.2) may develop psychiatric illnesses, including schizophrenia, schizoaffective disorder, and bipolar disorder, suggesting that lower gene dosage leads to a predisposition to these illnesses. In a bid to identify important regulatory polymorphisms (SNPs) that may emulate changes in gene dosage of the genes within the common deletion, we have analyzed the promoter region of 47 genes (44 of which encode a protein with known function) encoding proteins in and around 22q11 for sequence variants. A total of 33 of the promoters contained polymorphisms. Of those, 25 were cloned into a reporter gene vector, pGL3. The relative ability of each promoter haplotype to promote transcription of the luciferase gene was tested in each of two human cell lines (HEK293t and TE671), using a cotransfected CMV-SPAP plasmid as an internal control. Five genes (PRODH, DGCR14, GSTT2, SERPIND1, and a gene tentatively called DKFZP434P211) showed activity differences between haplotypes of greater than 1.5-fold. Of those, PRODH, which encodes proline dehydrogenase, has previously been highlighted in relation to schizophrenia, and the functional promoter polymorphism reported here may be involved in pathogenic mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 10 | Biochemistry 2004 Oct 43: 12539-48 |
| PMID | 15449943 |
| Title | Structures of the Escherichia coli PutA proline dehydrogenase domain in complex with competitive inhibitors. |
| Abstract | Proline dehydrogenase (PRODH) catalyzes the first step of proline catabolism, the flavin-dependent oxidation of proline to Delta(1)-pyrroline-5-carboxylate. Here we present a structure-based study of the PRODH active site of the multifunctional Escherichia coli proline utilization A (PutA) protein using X-ray crystallography, enzyme kinetic measurements, and site-directed mutagenesis. Structures of the PutA PRODH domain complexed with competitive inhibitors acetate (K(i) = 30 mM), L-lactate (K(i) = 1 mM), and L-tetrahydro-2-furoic acid (L-THFA, K(i) = 0.2 mM) have been determined to high-resolution limits of 2.1-2.0 A. The discovery of acetate as a competitive inhibitor suggests that the carboxyl is the minimum functional group recognized by the active site, and the structures show how the enzyme exploits hydrogen-bonding and nonpolar interactions to optimize affinity for the substrate. The PRODH/L-THFA complex is the first structure of PRODH with a five-membered ring proline analogue bound in the active site and thus provides new insights into substrate recognition and the catalytic mechanism. The ring of L-THFA is nearly parallel to the middle ring of the FAD isoalloxazine, with the inhibitor C5 atom 3.3 A from the FAD N5. This geometry suggests direct hydride transfer as a plausible mechanism. Mutation of conserved active site residue Leu432 to Pro caused a 5-fold decrease in k(cat) and a severe loss in thermostability. These changes are consistent with the location of Leu432 in the hydrophobic core near residues that directly contact FAD. Our results suggest that the molecular basis for increased plasma proline levels in schizophrenic subjects carrying the missense mutation L441P is due to decreased stability of human PRODH2. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 11 | Synapse 2004 Feb 51: 112-8 |
| PMID | 14618678 |
| Title | Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression. |
| Abstract | Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) may both be susceptibility genes for schizophrenia. As part of the evaluation of their roles in psychosis, we used reverse transcription-polymerase chain reaction to measure COMT and PRODH mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, major depression, and normal controls (n = 15 subjects in each group). We also genotyped two common COMT polymorphisms (-287A/G and 158Val/Met) which might affect its expression. Neither COMT nor PRODH mRNA abundance differed between diagnostic groups, nor when controls were compared with all psychotic patients. COMT mRNA levels were unrelated to COMT genotypes. We conclude that any involvement of COMT and PRODH genes in schizophrenia is not accompanied by significant alterations in their overall mRNA expression, at least in dorsolateral prefrontal cortex. As COMT and PRODH are both located on chromosome 22q11, the results also argue against the hypothesis that schizophrenia is associated with a decrease in expression of all 22q11 genes, as had been suggested by the high prevalence of psychosis in people with hemizygous 22q11 deletions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 12 | Wien. Klin. Wochenschr. 2004 Dec 116: 827-33 |
| PMID | 15690966 |
| Title | [In search of susceptibility genes for schizophrenia]. |
| Abstract | After the recent discovery and replication of several schizophrenia candidate regions on multiple chromosomes, susceptibility genes for schizophrenia could be identified for the first time. Each of these discoveries resulted from association studies within chromosomal regions first identified by linkage analyses. Within the last two years, the susceptibility genes Neuregulin1, Dysbindin, D-amino-acid-oxidase (DAAO) and G72 were discovered, which, in the variant forms, reduce glutamatergic activity in brain. Therefore, they are related to the so-called "Glutamate-hypothesis", which postulates a hypofunction of the glutamatergic system. Adults with VCFS (velo-cardio-facial-syndrome), where a deletion on chromosome 22q11 can be found, show a very high incidence of schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion. Within the VCFS-deleted region on chromosome 22q11, the genes coding for proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT) were also found to be significantly associated with schizophrenia. Proline is a pre-stage of glutamate, and in addition, it seems to be a neuromodulator of glutamatergic transmission in the brain. COMT is one of the two enzymes degrading catecholamines such as dopamine. Therefore, it plays a large role in the cortical dopamine metabolism. Furthermore, an association of schizophrenia with the gene RGS4 (regulator-of-G-protein-signaling-4), a modulator of the function of multiple G-protein-linked neurotransmitter receptors, was identified. Gene-expression-analyses of postmortem cerebral cortex (prefrontal) indicate that the transcription of RGS4 is diminished within schizophrenics. In accordance with the fact that schizophrenia is a disease with a multifactorial etiology, it should be emphasized that the described biological risk factors can increase susceptibility, but that none of them can cause the disease alone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 13 | Wien. Klin. Wochenschr. 2004 Dec 116: 827-33 |
| PMID | 15690966 |
| Title | [In search of susceptibility genes for schizophrenia]. |
| Abstract | After the recent discovery and replication of several schizophrenia candidate regions on multiple chromosomes, susceptibility genes for schizophrenia could be identified for the first time. Each of these discoveries resulted from association studies within chromosomal regions first identified by linkage analyses. Within the last two years, the susceptibility genes Neuregulin1, Dysbindin, D-amino-acid-oxidase (DAAO) and G72 were discovered, which, in the variant forms, reduce glutamatergic activity in brain. Therefore, they are related to the so-called "Glutamate-hypothesis", which postulates a hypofunction of the glutamatergic system. Adults with VCFS (velo-cardio-facial-syndrome), where a deletion on chromosome 22q11 can be found, show a very high incidence of schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion. Within the VCFS-deleted region on chromosome 22q11, the genes coding for proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT) were also found to be significantly associated with schizophrenia. Proline is a pre-stage of glutamate, and in addition, it seems to be a neuromodulator of glutamatergic transmission in the brain. COMT is one of the two enzymes degrading catecholamines such as dopamine. Therefore, it plays a large role in the cortical dopamine metabolism. Furthermore, an association of schizophrenia with the gene RGS4 (regulator-of-G-protein-signaling-4), a modulator of the function of multiple G-protein-linked neurotransmitter receptors, was identified. Gene-expression-analyses of postmortem cerebral cortex (prefrontal) indicate that the transcription of RGS4 is diminished within schizophrenics. In accordance with the fact that schizophrenia is a disease with a multifactorial etiology, it should be emphasized that the described biological risk factors can increase susceptibility, but that none of them can cause the disease alone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 14 | Brain Res. Mol. Brain Res. 2004 Dec 132: 95-104 |
| PMID | 15582150 |
| Title | The molecular genetics of the 22q11-associated schizophrenia. |
| Abstract | schizophrenia has a strong genetic component but the mode of inheritance of the disease is complex and in all likelihood involves interaction among multiple genes and also possibly environmental or stochastic factors. A number of studies have shown that the 22q11 deletion syndrome (22q11DS) is a true genetic subtype of schizophrenia and as such may play an extremely important role in deciphering the genetic basis of schizophrenia. Microdeletions of the 22q11 locus are associated with a staggering increased risk to develop schizophrenia. The same locus has also been implicated by some linkage studies. Systematic examination of individual genes from the 1.5 Mb critical region has identified so far the PRODH and ZDHHC8 as strong candidate schizophrenia susceptibility genes from this locus. Discovery of these genes implicates neuromodulatory aminoacids and protein palmitoylation as important for disease development. Other genes, including the gene encoding for COMT, have been implicated by candidate gene approaches. It therefore appears that the 22q11-associated schizophrenia may have the characteristics of a contiguous gene syndrome, where deficiency in more than one gene contributes to the strikingly increased disease risk. Mouse models for individual candidate genes will provide the investigators with the opportunity to start understanding the function of these genes and how they may impact on schizophrenia. Mouse models that carry long-range deletions will likely capture the interactions among the culprit genes and help explain the genetic contribution of this locus to the high risk for schizophrenia. In-depth human and animal model studies of 22q11DS promise to answer critical questions relating to the devastating illness of schizophrenia, whose causes remain largely unknown. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 15 | Malays J Med Sci 2004 Jul 11: 3-11 |
| PMID | 22973121 |
| Title | The genetics of schizophrenia. |
| Abstract | schizophrenia is a complex biological disorder with multifactorial mode of transmission where non-genetic determinants are also play important role. It is now clear that it involves combined effect of many genes, each conferring a small increase in liability to the illness. Thus no causal disease genes or single gene of major effects, only susceptible genes are operating. Given this complexity, it comes as no surprise of the difficulty to find susceptible genes. However, schizophrenia genes have been found at last. Recent studies on molecular genetics of schizophrenia which focused on positional and functional candidate genes postulated to be associated with schizophrenia are beginning to produce findings of great interest. These include neuregulin (NRG-1, 8p12-21), dysbindin, (DTNBP1,6p22.3), G72 (13q34) / D-amino acid oxidase (DAAO,12q24), proline dehydrogenase (PRODH-2, 22q11.21), catechol-O-methyltransferase (COMT, 22q11.21), regulator of G protein signaling (RGS-4), 5HT2A and dopamine D3 receptor (DRD3). Applications of microarrays methods were able to locate positional candidate genes related to dopaminergic, serotonergic and glutamatergic neurotransmission. New genome scan project, seen in the light of previous scans, provide support for schizophrenia candidate region on chromosome 1q, 2q, 5q, 6p, 8p, 10p, 13q,15q and 22q. Other reports described including the application of LD mapping and positional cloning technique, microarray technology and efforts to develop quantitative phenotype. More exciting finding is expected in near future with the completion of Hap Map project. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 16 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Aug 129B: 13-5 |
| PMID | 15274030 |
| Title | Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population. |
| Abstract | Haploinsufficiency for or mutation in at least one gene from the velocardiofacial syndrome (VCFS) region at chromosome 22q11 is implicated in psychosis. Linkage disequilibrium mapping of the region in patients identified a segment containing two genes, proline dehydrogenase (PRODH) and DGCR6, as candidates [Liu et al., 2002a] and by analysis of additional polymorphisms the PRODH gene was associated with schizophrenia in adult and early onset patients. In the present study we provide additional evidence in support of genetic association between PRODH and schizophrenia in a Chinese population. We analyzed the PRODH gene in a samples of schizophrenic patients and their families from Sichuan, SW China consisting of 528 family trios and sibling pairs. We genotyped six SNPs, PRODH*1195C-->T, PRODH*1482C-->T, PRODH*1483A-->G, PRODH*1766A-->G, PRODH*1852G-->A PRODH*1945T-->C, two of which (PRODH*1483A-->G and PRODH*1852G-->A) have not been previously reported. We found association with schizophrenia for two haplotypes consisting of PRODH*1945T-->C and PRODH*1852G-->A (Global P = 0.006), and PRODH*1852G-->A and PRODH*1766A-->G (Global P = 0.01) which include one of the newly identified markers. After six-fold Bonferroni correction for multiple testing the PRODH*1945T-C/PRODH*1852G-A haplotypes remained significant. This is a sub-haplotype of the PRODH haplotype previously associated with schizophrenia and it also maps to the 3' region of the gene, indicating that this is the region most likely to contain the underlying risk alleles. Overall this finding supports a role for the PRODH locus in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 17 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Aug 129B: 13-5 |
| PMID | 15274030 |
| Title | Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population. |
| Abstract | Haploinsufficiency for or mutation in at least one gene from the velocardiofacial syndrome (VCFS) region at chromosome 22q11 is implicated in psychosis. Linkage disequilibrium mapping of the region in patients identified a segment containing two genes, proline dehydrogenase (PRODH) and DGCR6, as candidates [Liu et al., 2002a] and by analysis of additional polymorphisms the PRODH gene was associated with schizophrenia in adult and early onset patients. In the present study we provide additional evidence in support of genetic association between PRODH and schizophrenia in a Chinese population. We analyzed the PRODH gene in a samples of schizophrenic patients and their families from Sichuan, SW China consisting of 528 family trios and sibling pairs. We genotyped six SNPs, PRODH*1195C-->T, PRODH*1482C-->T, PRODH*1483A-->G, PRODH*1766A-->G, PRODH*1852G-->A PRODH*1945T-->C, two of which (PRODH*1483A-->G and PRODH*1852G-->A) have not been previously reported. We found association with schizophrenia for two haplotypes consisting of PRODH*1945T-->C and PRODH*1852G-->A (Global P = 0.006), and PRODH*1852G-->A and PRODH*1766A-->G (Global P = 0.01) which include one of the newly identified markers. After six-fold Bonferroni correction for multiple testing the PRODH*1945T-C/PRODH*1852G-A haplotypes remained significant. This is a sub-haplotype of the PRODH haplotype previously associated with schizophrenia and it also maps to the 3' region of the gene, indicating that this is the region most likely to contain the underlying risk alleles. Overall this finding supports a role for the PRODH locus in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 18 | Br. Med. Bull. 2005 -1 73-74: 107-22 |
| PMID | 16365481 |
| Title | Psychiatric genetics--the new era: genetic research and some clinical implications. |
| Abstract | Impressive advances in the last decade have been made in the genetics and neuroscience of neuropsychiatric illness. Synergies between complex genetics, elaboration of intermediate phenotypes (Egan et al. (2004) schizophrenia. London: Blackwell) and novel applications in neuroimaging (Bookheimer et al. (2000) N Engl J Med, 343, 450-456) are revealing the effects of positively associated disease alleles on aspects of neurological function. Genes such as NRG-1, DISC1, RGS4, COMT, PRODH, DTNBP1, G72, DAAO, GRM3 (Harrison and Weinberger (2005) Mol Psychiatry, 10, 40-68) and others have been implicated in schizophrenia along with 5-HTTPR (Ogilvie et al. (1996) Lancet, 347, 731-733; Caspi et al. (2003) Science, 301, 386-389) and BDNF (Geller et al. (2004) Am J Psychiatry, 161, 1698-1700) in affective disorders. As the genetics and complex neurocircuits of these and disorders are being untangled, parallel applications in pharmacogenomics and gene-based drug metabolism are shaping a drive for personalized medicine. Genetic research and pharmacogenomics suggest that the subcategorization of individuals based on various sets of susceptibility alleles will make the treatment of neuropsychiatric and other illnesses more predictable and effective. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 19 | Nat. Neurosci. 2005 Nov 8: 1586-94 |
| PMID | 16234811 |
| Title | Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. |
| Abstract | Microdeletions of 22q11.2 represent one of the highest known genetic risk factors for schizophrenia. It is likely that more than one gene contributes to the marked risk associated with this locus. Two of the candidate risk genes encode the enzymes proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT), which modulate the levels of a putative neuromodulator (L-proline) and the neurotransmitter dopamine, respectively. Mice that model the state of PRODH deficiency observed in humans with schizophrenia show increased neurotransmitter release at glutamatergic synapses as well as deficits in associative learning and response to psychomimetic drugs. Transcriptional profiling and pharmacological manipulations identified a transcriptional and behavioral interaction between the PRODH and Comt genes that is likely to represent a homeostatic response to enhanced dopaminergic signaling in the frontal cortex. This interaction modulates a number of schizophrenia-related phenotypes, providing a framework for understanding the high disease risk associated with this locus, the expression of the phenotype, or both. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 20 | Nihon Shinkei Seishin Yakurigaku Zasshi 2005 Apr 25: 79-84 |
| PMID | 16220657 |
| Title | [Chromosome 22q11 and schizophrenia]. |
| Abstract | Several human chromosomal regions have been identified as candidate regions that play a role in schizophrenia. Deletion or duplication of chromosome 22q11 is associated with velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), a disorder associated with high rates of schizophrenia as well as physical abnormalities (i.e., cardiovascular, parathyroid, thymic and craniofacial abnormalities). Recent mouse studies have identified several candidate genes for VCFS/DGS within the mouse homologue chromosome 16. Deletion of Tbx1, PRODH and Comt within mouse chromosome 16 causes several physical and behavioral features of VCFS/DGS. As VCFS/DGS is likely to represent a genetic subtype of schizophrenia, pinpointing the genetic basis for this specific subtype will contribute to a better understanding of this neuropsychiatric disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 21 | Fortschr Neurol Psychiatr 2005 Nov 73 Suppl 1: S44-50 |
| PMID | 16270244 |
| Title | [Genetic risk factors in schizophrenia]. |
| Abstract | The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt based on the findings of epidemiological studies. By means of a complex mode of transmission, it is likely that several genes with weak to moderate effect jointly constitute a genetic basis for a vulnerability to schizophrenia that may well vary for different individuals. Other organic and psychosocial factors also play an individually different -- in some cases significant -- role in terms of pathogenesis, as a result of which an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics. Molecular genetic methods consist in linkage analyses and association analyses. Positive linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q. By themselves, individual mutations contribute little to the range of schizophrenic feature characteristics, it was not possible -- irrespective of some subtypes -- to replicate genes of major effect. From the large number of possible candidate genes, although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT, PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case of a homogeneous genotype as much as by the possibility of inter-individually homogeneous phenotypical characteristics in case of schizophrenia-relevant heterotype in the genome. With the aid of the concept of endo-phenotypes, based on neurobiological phenomena, it might be possible to take a more direct approach that leads from relevant mutations to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological aspects leads to difficulties in explaining these complex disorder profiles. schizophrenic diseases require an explanatory approach that also incorporates personality and developmental psychological aspects from the outset, if the aim is not to restrict type of schizophrenic disease exclusively to loci of molecular genetic changes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 22 | Fortschr Neurol Psychiatr 2005 Nov 73 Suppl 1: S44-50 |
| PMID | 16270244 |
| Title | [Genetic risk factors in schizophrenia]. |
| Abstract | The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt based on the findings of epidemiological studies. By means of a complex mode of transmission, it is likely that several genes with weak to moderate effect jointly constitute a genetic basis for a vulnerability to schizophrenia that may well vary for different individuals. Other organic and psychosocial factors also play an individually different -- in some cases significant -- role in terms of pathogenesis, as a result of which an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics. Molecular genetic methods consist in linkage analyses and association analyses. Positive linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q. By themselves, individual mutations contribute little to the range of schizophrenic feature characteristics, it was not possible -- irrespective of some subtypes -- to replicate genes of major effect. From the large number of possible candidate genes, although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT, PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case of a homogeneous genotype as much as by the possibility of inter-individually homogeneous phenotypical characteristics in case of schizophrenia-relevant heterotype in the genome. With the aid of the concept of endo-phenotypes, based on neurobiological phenomena, it might be possible to take a more direct approach that leads from relevant mutations to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological aspects leads to difficulties in explaining these complex disorder profiles. schizophrenic diseases require an explanatory approach that also incorporates personality and developmental psychological aspects from the outset, if the aim is not to restrict type of schizophrenic disease exclusively to loci of molecular genetic changes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 23 | Fortschr Neurol Psychiatr 2005 Nov 73 Suppl 1: S44-50 |
| PMID | 16270244 |
| Title | [Genetic risk factors in schizophrenia]. |
| Abstract | The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt based on the findings of epidemiological studies. By means of a complex mode of transmission, it is likely that several genes with weak to moderate effect jointly constitute a genetic basis for a vulnerability to schizophrenia that may well vary for different individuals. Other organic and psychosocial factors also play an individually different -- in some cases significant -- role in terms of pathogenesis, as a result of which an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics. Molecular genetic methods consist in linkage analyses and association analyses. Positive linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q. By themselves, individual mutations contribute little to the range of schizophrenic feature characteristics, it was not possible -- irrespective of some subtypes -- to replicate genes of major effect. From the large number of possible candidate genes, although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT, PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case of a homogeneous genotype as much as by the possibility of inter-individually homogeneous phenotypical characteristics in case of schizophrenia-relevant heterotype in the genome. With the aid of the concept of endo-phenotypes, based on neurobiological phenomena, it might be possible to take a more direct approach that leads from relevant mutations to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological aspects leads to difficulties in explaining these complex disorder profiles. schizophrenic diseases require an explanatory approach that also incorporates personality and developmental psychological aspects from the outset, if the aim is not to restrict type of schizophrenic disease exclusively to loci of molecular genetic changes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 24 | Am. J. Hum. Genet. 2005 Mar 76: 409-20 |
| PMID | 15662599 |
| Title | Functional consequences of PRODH missense mutations. |
| Abstract | PRODH maps to 22q11 in the region deleted in the velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS) and encodes proline oxidase (POX), a mitochondrial inner-membrane enzyme that catalyzes the first step in the proline degradation pathway. At least 16 PRODH missense mutations have been identified in studies of type I hyperprolinemia (HPI) and schizophrenia, 10 of which are present at polymorphic frequencies. The functional consequences of these missense mutations have been inferred by evolutionary conservation, but none have been tested directly. Here, we report the effects of these mutations on POX activity. We find that four alleles (R185Q, L289M, A455S, and A472T) result in mild (<30%), six (Q19P, A167V, R185W, D426N, V427M, and R431H) in moderate (30%-70%), and five (P406L, L441P, R453C, T466M, and Q521E) in severe (>70%) reduction in POX activity, whereas one (Q521R) increases POX activity. The POX encoded by one severe allele (T466M) shows in vitro responsiveness to high cofactor (flavin adenine dinucleotide) concentrations. Although there is limited information on plasma proline levels in individuals of known PRODH genotype, extant data suggest that severe hyperprolinemia (>800 microM) occurs in individuals with large deletions and/or PRODH missense mutations with the most-severe effect on function (L441P and R453C), whereas modest hyperprolinemia (300-500 microM) is associated with PRODH alleles with a moderate reduction in activity. Interestingly, three of the four alleles associated with or found in schizophrenia (V427M, L441P, and R453C) resulted in severe reduction of POX activity and hyperprolinemia. These observations plus the high degree of polymorphism at the PRODH locus are consistent with the hypothesis that reduction in POX function is a risk factor for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 25 | Mol. Psychiatry 2005 May 10: 479-85 |
| PMID | 15494707 |
| Title | Hyperprolinemia is a risk factor for schizoaffective disorder. |
| Abstract | DNA sequence variations within the 22q11 DiGeorge chromosomal region are likely to confer susceptibility to psychotic disorders. In a previous report, we identified several heterozygous alterations, including a complete deletion, of the proline dehydrogenase (PRODH) gene, which were associated with moderate hyperprolinemia in a subset of DSM III schizophrenic patients. Our objective was (i) to determine whether hyperprolinemia is associated with increased susceptibility for any of three psychiatric conditions (schizophrenia, schizoaffective disorder and bipolar disorder) and (ii) to establish a correlation between hyperprolinemia and PRODH genotypes. We have conducted a case-control study including 114 control subjects, 188 patients with schizophrenia, 63 with schizoaffective disorder and 69 with bipolar disorder. We report that, taking into account a confounding effect due to valproate treatment, hyperprolinemia is a risk factor for DSM IIIR schizoaffective disorder (P=0.02, Odds ratio=4.6, 95% confidence interval 1.3-16.3). We did not detect 22q11 interstitial deletions associated with the DiGeorge syndrome among the 320 patients of our sample and we found no association between common PRODH polymorphisms and any of the psychotic disorders. In contrast, we found that five rare PRODH alterations (including a complete PRODH deletion and four missense substitutions) were associated with hyperprolinemia. In several cases, two variations were present simultaneously, either in cis or trans in the same subject. A total of 11 from 30 hyperprolinemic subjects bore at least one genetic variation associated with hyperprolinemia. This study demonstrates that moderate hyperprolinemia is an intermediate phenotype associated with certain forms of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 26 | Mol. Psychiatry 2005 May 10: 479-85 |
| PMID | 15494707 |
| Title | Hyperprolinemia is a risk factor for schizoaffective disorder. |
| Abstract | DNA sequence variations within the 22q11 DiGeorge chromosomal region are likely to confer susceptibility to psychotic disorders. In a previous report, we identified several heterozygous alterations, including a complete deletion, of the proline dehydrogenase (PRODH) gene, which were associated with moderate hyperprolinemia in a subset of DSM III schizophrenic patients. Our objective was (i) to determine whether hyperprolinemia is associated with increased susceptibility for any of three psychiatric conditions (schizophrenia, schizoaffective disorder and bipolar disorder) and (ii) to establish a correlation between hyperprolinemia and PRODH genotypes. We have conducted a case-control study including 114 control subjects, 188 patients with schizophrenia, 63 with schizoaffective disorder and 69 with bipolar disorder. We report that, taking into account a confounding effect due to valproate treatment, hyperprolinemia is a risk factor for DSM IIIR schizoaffective disorder (P=0.02, Odds ratio=4.6, 95% confidence interval 1.3-16.3). We did not detect 22q11 interstitial deletions associated with the DiGeorge syndrome among the 320 patients of our sample and we found no association between common PRODH polymorphisms and any of the psychotic disorders. In contrast, we found that five rare PRODH alterations (including a complete PRODH deletion and four missense substitutions) were associated with hyperprolinemia. In several cases, two variations were present simultaneously, either in cis or trans in the same subject. A total of 11 from 30 hyperprolinemic subjects bore at least one genetic variation associated with hyperprolinemia. This study demonstrates that moderate hyperprolinemia is an intermediate phenotype associated with certain forms of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 27 | Schizophr. Res. 2006 Jun 84: 253-71 |
| PMID | 16632332 |
| Title | Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. |
| Abstract | Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 28 | Psychiatr. Genet. 2006 Dec 16: 229-30 |
| PMID | 17106420 |
| Title | Bipolar 1 disorder is not associated with the RGS4, PRODH, COMT and GRK3 genes. |
| Abstract | Although current psychiatric nosology separates bipolar disorder and schizophrenia into non-overlapping categories, there is growing evidence of a partial aetiological overlap between them from linkage, genetic epidemiology and molecular genetics studies. Thus, it is important to determine whether genes implicated in the aetiology of schizophrenia play a role in bipolar disorder, and vice versa. In this study we investigated a total of 15 single nucleotide polymorphisms (SNPs), and all possible haplotypes, of genes that have been previously implicated in schizophrenia or bipolar disorder - RGS4, PRODH, COMT and GRK3 - in a sample of 213 cases with bipolar affective disorder type 1 and 197 controls from Scotland. We analysed the polymorphisms allele-wise, genotype-wise and, for each gene, haplotype-wise but obtained no result that reached nominal significance (p<0.05) for an association with the disease status. In conclusion, we could not find evidence of association between RGS4, PRODH, COMT and GRK3 genes and bipolar affective disorder 1 in the Scottish population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 29 | Schizophr. Res. 2006 Oct 87: 21-7 |
| PMID | 16860541 |
| Title | Analysis of ProDH, COMT and ZDHHC8 risk variants does not support individual or interactive effects on schizophrenia susceptibility. |
| Abstract | Synergistic interaction between genes on chromosome 22q11 recently has been proposed as a possible mechanism which could confer increased risk for schizophrenia. Based on this hypothesis, our study aimed to explore main, cis- and trans-interacting effects of three candidate genes on 22q11, PRODH, COMT and ZDHHC8. We selected four putative risk variants, residing within these genes, PRODH 1945, PRODH 2026, COMT ValMet and ZDHHC8 rs175174, and studied these in a large family-based schizophrenia association sample of European origin (488 Bulgarian parent-offspring trios). The presence of interaction between the variants was tested by conditional logistic regression analysis based on a case-pseudocontrol design. Our study did not find statistical evidence for allelic (investigation of PRODH markers only), genotypic, haplotypic, or interactive effects between PRODH, COMT and ZDHHC8. Our data do not support the hypothesis that an interaction between these genes influences susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 30 | Schizophr. Res. 2006 Dec 88: 251-9 |
| PMID | 17008057 |
| Title | Altered expression of hippocampal dentate granule neuron genes in a mouse model of human 22q11 deletion syndrome. |
| Abstract | Hemizygous deletion of a 3 Mb region of 22q11.2 is found in 1/4000 humans and produces 22q11 deletion syndrome (22q11DS). Up to 35% of 22q11DS patients develop schizophrenia, making it the second highest risk factor for schizophrenia. A mouse model for 22q11DS, the Df1/+ mouse, carries a hemizygous deletion in a region syntenic with the human deletion. Df1/+ mice are mostly viable but display deficits in prepulse inhibition and learning and memory, two common traits of schizophrenia thought to result, at least in part, from defects in hippocampal neurons. We used oligonucleotide microarrays and QRT-PCR to evaluate gene expression changes in hippocampal dentate granule neurons of Df1/+ mice versus wild-type littermates (n=12/group). The expression of only 287 genes changed with p value significance below 0.05 by microarray, yet 12 of the 21 Df1 region genes represented on the array showed highly significantly reduced expression compared to wild-type controls (33% on average, p values from 10(-3) to 10(-7)). Variants in two of these genes, COMT and PRODH, have been linked with schizophrenia. Overlap of the 287 genes with the reportedly reduced expression of mitochondrial, ubiquitin/proteasome, and synaptic plasticity genes in schizophrenia dentate granule neurons, was not significant. However, modest increases in expression of mitochondrial electron transport genes were observed in the Df1/+ mice. This perhaps indicates a compensation for mitochondrial dysfunction caused by the strongly reduced expression of the Df1 region-encoded mitochondrial enzymes proline dehydrogenase (PRODH) and thioredoxin reductase 2 (Txnrd2). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 31 | Eur. J. Hum. Genet. 2006 Oct 14: 1130-5 |
| PMID | 16791139 |
| Title | Association study of the G-protein signaling 4 (RGS4) and proline dehydrogenase (PRODH) genes with schizophrenia: a meta-analysis. |
| Abstract | schizophrenia is a devastating psychiatric disease that affects up to 1% of the population worldwide. Recent studies suggested that schizophrenia might result from the hypofunction of glutamatergic neurotransmission. Systematic positional, expression and functional studies have implicated the regulator of G-protein signaling 4 (RGS4) and proline dehydrogenase (PRODH) genes as promising and novel candidates for explaining schizophrenia. However, the findings of association studies tend to vary depending on the different populations on which they have been conducted. To reconcile this conflict of evidence, we combined all available population-based and family-based studies up to July 2005 involving eight polymorphisms. However, this meta-analysis did not find statistically significant evidence for association between the two glutamate-related genes and schizophrenia on the basis of either allelic or genotypic analysis. This may be the first systematic meta-analysis study based on RGS4 and PRODH. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 32 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Mar 141B: 192 |
| PMID | 16389584 |
| Title | Hyperprolinemia is not associated with childhood onset schizophrenia. |
| Abstract | In a previous report [Jacquet et al., 2005] we have shown that mild to moderate hyperprolinemia resulting from several alterations (either a complete deletion or missense mutations) of the proline dehydrogenase (PRODH) gene located on chromosome 22q11 is a risk factor for schizoaffective disorder but not for DSM3 R schizophrenia or bipolar disorder. We now report that hyperprolinemia is not associated with childhood onset schizophrenia (COS). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 33 | Cell. Physiol. Biochem. 2007 -1 20: 687-702 |
| PMID | 17982252 |
| Title | Molecular mechanisms of schizophrenia. |
| Abstract | schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 34 | Cell. Physiol. Biochem. 2007 -1 20: 687-702 |
| PMID | 17982252 |
| Title | Molecular mechanisms of schizophrenia. |
| Abstract | schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 35 | Psychiatry Res 2007 Sep 153: 7-15 |
| PMID | 17604122 |
| Title | A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population. |
| Abstract | Previous studies have suggested that catechol-O-methyltransferase (COMT), proline dehydrogenase (PRODH), and brain-derived neurotrophic factor (BDNF) genes are possible susceptibility genes for schizophrenia. We hypothesized that these genes are also associated with schizotypal traits, which are heritable and related to schizophrenia. We genotyped five single nucleotide polymorphism (SNPs) from the COMT, PRODH and BDNF genes, and performed a series of association analyses between alleles, genotypes or haplotypes, and quantitative schizotypal trait scores derived from the schizotypal Personality Questionnaire (SPQ), in 465 Chinese healthy subjects. We found that 'years of education' was a major influence on seven out of nine schizotypal components, three schizotypal factors and the total SPQ scores. Molecular genetic analysis of COMT, PRODH and BDNF genes showed no significant effects of any variants on schizotypal components or factors of SPQ after correction for multiple testing, although there were weak association between COMT Val158Met (rs4680G/A) and the odd speech subscale (allele-wise, P=0.04; genotype-wise, P=0.049), between COMT Val158Met (rs4680G/A) and the suspiciousness subscale (genotype-wise, P=0.024), and between BDNF Val66Met and the Factor 2 interpersonal measure (genotype-wise, P=0.027) before correction. Furthermore, we found SNP Val158Met (rs4680) of the COMT gene significantly influenced the scores of some of schizotypal traits including total SPQ score, the disorganization factor and the constricted affect subscale in male subjects only. However, the effect was in the opposite direction of an earlier association with the SPQ reported by Avramopoulos et al. [Avramopoulos, D., Stefanis, N.C., Hantoumi, I., Smyrnis, N., Evdokimidis, I., Stefanis, C.N., 2002. Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. Molecular Psychiatry 7, 706-711]. We conclude that SNP Val158Met (rs4680) in the COMT gene may be associated with some schizotypal traits in male subjects, but our results are not conclusive. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 36 | Psychiatry Res 2007 Sep 153: 7-15 |
| PMID | 17604122 |
| Title | A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population. |
| Abstract | Previous studies have suggested that catechol-O-methyltransferase (COMT), proline dehydrogenase (PRODH), and brain-derived neurotrophic factor (BDNF) genes are possible susceptibility genes for schizophrenia. We hypothesized that these genes are also associated with schizotypal traits, which are heritable and related to schizophrenia. We genotyped five single nucleotide polymorphism (SNPs) from the COMT, PRODH and BDNF genes, and performed a series of association analyses between alleles, genotypes or haplotypes, and quantitative schizotypal trait scores derived from the schizotypal Personality Questionnaire (SPQ), in 465 Chinese healthy subjects. We found that 'years of education' was a major influence on seven out of nine schizotypal components, three schizotypal factors and the total SPQ scores. Molecular genetic analysis of COMT, PRODH and BDNF genes showed no significant effects of any variants on schizotypal components or factors of SPQ after correction for multiple testing, although there were weak association between COMT Val158Met (rs4680G/A) and the odd speech subscale (allele-wise, P=0.04; genotype-wise, P=0.049), between COMT Val158Met (rs4680G/A) and the suspiciousness subscale (genotype-wise, P=0.024), and between BDNF Val66Met and the Factor 2 interpersonal measure (genotype-wise, P=0.027) before correction. Furthermore, we found SNP Val158Met (rs4680) of the COMT gene significantly influenced the scores of some of schizotypal traits including total SPQ score, the disorganization factor and the constricted affect subscale in male subjects only. However, the effect was in the opposite direction of an earlier association with the SPQ reported by Avramopoulos et al. [Avramopoulos, D., Stefanis, N.C., Hantoumi, I., Smyrnis, N., Evdokimidis, I., Stefanis, C.N., 2002. Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. Molecular Psychiatry 7, 706-711]. We conclude that SNP Val158Met (rs4680) in the COMT gene may be associated with some schizotypal traits in male subjects, but our results are not conclusive. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 37 | Psychiatry Res 2007 Sep 153: 7-15 |
| PMID | 17604122 |
| Title | A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population. |
| Abstract | Previous studies have suggested that catechol-O-methyltransferase (COMT), proline dehydrogenase (PRODH), and brain-derived neurotrophic factor (BDNF) genes are possible susceptibility genes for schizophrenia. We hypothesized that these genes are also associated with schizotypal traits, which are heritable and related to schizophrenia. We genotyped five single nucleotide polymorphism (SNPs) from the COMT, PRODH and BDNF genes, and performed a series of association analyses between alleles, genotypes or haplotypes, and quantitative schizotypal trait scores derived from the schizotypal Personality Questionnaire (SPQ), in 465 Chinese healthy subjects. We found that 'years of education' was a major influence on seven out of nine schizotypal components, three schizotypal factors and the total SPQ scores. Molecular genetic analysis of COMT, PRODH and BDNF genes showed no significant effects of any variants on schizotypal components or factors of SPQ after correction for multiple testing, although there were weak association between COMT Val158Met (rs4680G/A) and the odd speech subscale (allele-wise, P=0.04; genotype-wise, P=0.049), between COMT Val158Met (rs4680G/A) and the suspiciousness subscale (genotype-wise, P=0.024), and between BDNF Val66Met and the Factor 2 interpersonal measure (genotype-wise, P=0.027) before correction. Furthermore, we found SNP Val158Met (rs4680) of the COMT gene significantly influenced the scores of some of schizotypal traits including total SPQ score, the disorganization factor and the constricted affect subscale in male subjects only. However, the effect was in the opposite direction of an earlier association with the SPQ reported by Avramopoulos et al. [Avramopoulos, D., Stefanis, N.C., Hantoumi, I., Smyrnis, N., Evdokimidis, I., Stefanis, C.N., 2002. Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. Molecular Psychiatry 7, 706-711]. We conclude that SNP Val158Met (rs4680) in the COMT gene may be associated with some schizotypal traits in male subjects, but our results are not conclusive. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 38 | Hum. Genet. 2007 Feb 120: 837-45 |
| PMID | 17028864 |
| Title | Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome. |
| Abstract | 22q11 Deletion syndrome (22q11DS) is a common microdeletion syndrome with variable expression, including congenital and later onset conditions such as schizophrenia. Most studies indicate that expression does not appear to be related to length of the deletion but there is limited information on the endpoints of even the common deletion breakpoint regions in adults. We used a real-time quantitative PCR (qPCR) approach to fine map 22q11.2 deletions in 44 adults with 22q11DS, 22 with schizophrenia (SZ; 12 M, 10 F; mean age 35.7 SD 8.0 years) and 22 with no history of psychosis (NP; 8 M, 14 F; mean age 27.1 SD 8.6 years). QPCR data were consistent with clinical FISH results using the TUPLE1 or N25 probes. Two subjects (one SZ, one NP) negative for clinical FISH had atypical 22q11.2 deletions confirmed by FISH using the RP11-138C22 probe. Most (n = 34; 18 SZ, 16 NP) subjects shared a common 3 Mb hemizygous 22q11.2 deletion. However, eight subjects showed breakpoint variability: a more telomeric proximal breakpoint (n = 2), or more centromeric (n = 3) or more telomeric distal breakpoint (n = 3). One NP subject had a proximal nested 1.4 Mb deletion. COMT and TBX1 were deleted in all 44 subjects, and PRODH in 40 subjects (19 SZ, 21 NP). The results delineate proximal and distal breakpoint variants in 22q11DS. Neither deletion extent nor PRODH haploinsufficiency appeared to explain the clinical expression of schizophrenia in the present study. Further studies are needed to elucidate the molecular basis of schizophrenia and clinical heterogeneity in 22q11DS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 39 | Neurosci Biobehav Rev 2007 -1 31: 60-78 |
| PMID | 16782199 |
| Title | Susceptibility genes for schizophrenia: characterisation of mutant mouse models at the level of phenotypic behaviour. |
| Abstract | A wealth of evidence indicates that schizophrenia is heritable. However, the genetic mechanisms involved are poorly understood. Furthermore, it may be that genes conferring susceptibility interact with one another and with non-genetic factors to modulate risk status and/or the expression of symptoms. Genome-wide scanning and the mapping of several regions linked with risk for schizophrenia have led to the identification of several putative susceptibility genes including neuregulin-1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signalling 4 (RGS4), catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH) and disrupted-in-schizophrenia 1 (DISC1). Genetic animal models involving targeted mutation via gene knockout or transgenesis have the potential to inform on the role of a given susceptibility gene on the development and behaviour of the whole organism and on whether disruption of gene function is associated with schizophrenia-related structural and functional deficits. This review focuses on data regarding the behavioural phenotype of mice mutant for schizophrenia susceptibility genes identified by positional candidate analysis and the study of chromosomal abnormalities. We also consider methodological issues that are likely to influence phenotypic effects, as well as the limitations associated with existing molecular techniques. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 40 | Brain Dev. 2007 Oct 29: 547-52 |
| PMID | 17412540 |
| Title | Early neurological phenotype in 4 children with biallelic PRODH mutations. |
| Abstract | Hyperprolinemia type I (HPI) results from a deficiency of proline oxidase (POX), involved in the first step in the conversion of proline to glutamate. Diverse phenotypes were described in patients with HPI, prior to the identification of the POX gene (PRODH): whereas various patients were asymptomatic, others had neurological and extraneurological defects. The PRODH gene is located in the region deleted in velocardiofacial syndrome (VCFS). Heterozygous and homozygous mutations have been identified in patients with variable hyperprolinemia and various features (patients with schizophrenia, chromosome 22q11 microdeletions and/or neurological defects). A functional study has divided the PRODH missense mutations into three groups: those leading to mild, moderate, or severe reduction of POX activity. In this study, we report four unrelated children with HPI and a homogeneous severe neurological phenotype. We identified biallelic abnormalities in PRODH in these patients that led to severe reduction of POX activity. These included missense and non-sense mutations, deletions of PRODH and a 22q11 microdeletion. Four other children have been reported with severe biallelic PRODH mutations. The phenotype of these eight patients associates early psychomotor development delay with predominant cognitive defects, autistic features and epilepsy. Their values of hyperprolinemia ranged from 400 to 2200 micromol/L. Patients with biallelic PRODH alterations resulting in severely impaired POX activity had an early onset and severe neurological features. Thus, children with this phenotype and those with a microdeletion in chromosome 22q11, especially those with mental retardation and autistic features, should be tested for hyperprolinemia. Hyperprolinemic patients should be screened for PRODH mutations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 41 | Mol. Psychiatry 2008 Sep 13: 873-7 |
| PMID | 18195713 |
| Title | Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. |
| Abstract | The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 42 | Dev Disabil Res Rev 2008 -1 14: 26-34 |
| PMID | 18636634 |
| Title | Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome. |
| Abstract | There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk for the development of schizophrenia, with only a greater risk conferred by being the child of two parents with schizophrenia or the monozygotic co-twin of an affected individual. Both linkage and association studies of people with schizophrenia have implicated several susceptibility genes, of which three are in the 22q11.2 region; catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH), and Gnb1L. In addition, variation in Gnb1L is associated with the presence of psychosis in males with 22q11.2DS. In mouse models of 22q11.2DS, haploinsufficiency of Tbx1 and Gnb1L is associated with reduced prepulse inhibition, a schizophrenia endophenotype. The study of 22q11.2DS provides an attractive model to increase our understanding of the development and pathogenesis of schizophrenia and other psychiatric disorders in 22q11.2DS and in wider population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 43 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 654-7 |
| PMID | 18163391 |
| Title | PRODH gene is associated with executive function in schizophrenic families. |
| Abstract | The aim of this study was to investigate the relationship between polymorphisms in the PRODH and COMT genes and selected neurocognitive functions. Six SNPs in PRODH and two SNPs in COMT were genotyped in 167 first-episode schizophrenic families who had been assessed by a set of 14 neuropsychological tests. Neuropsychological measures were selected as quantitative traits for association analysis. The haplotype of SNPs PRODH 1945T/C and PRODH 1852G/A was associated with impaired performance on the Tower of Hanoi, a problem-solving task mainly reflecting planning capacity. There was no significant evidence for association with any other neuropsychological traits for other SNPs or haplotypes of paired SNPs in the two genes. This study takes previous findings of association between PRODH and schizophrenia further by associating variation within the gene with performance on a neurocognitive trait characteristic of the illness. It fails to confirm previous reports of an association between COMT and cognitive function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 44 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 654-7 |
| PMID | 18163391 |
| Title | PRODH gene is associated with executive function in schizophrenic families. |
| Abstract | The aim of this study was to investigate the relationship between polymorphisms in the PRODH and COMT genes and selected neurocognitive functions. Six SNPs in PRODH and two SNPs in COMT were genotyped in 167 first-episode schizophrenic families who had been assessed by a set of 14 neuropsychological tests. Neuropsychological measures were selected as quantitative traits for association analysis. The haplotype of SNPs PRODH 1945T/C and PRODH 1852G/A was associated with impaired performance on the Tower of Hanoi, a problem-solving task mainly reflecting planning capacity. There was no significant evidence for association with any other neuropsychological traits for other SNPs or haplotypes of paired SNPs in the two genes. This study takes previous findings of association between PRODH and schizophrenia further by associating variation within the gene with performance on a neurocognitive trait characteristic of the illness. It fails to confirm previous reports of an association between COMT and cognitive function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 45 | Genes Brain Behav. 2008 Feb 7: 61-9 |
| PMID | 17504246 |
| Title | Genetic variation in COMT and PRODH is associated with brain anatomy in patients with schizophrenia. |
| Abstract | Haploinsufficiency of 22q11 genes including catechol-O-methyltransferase (COMT) and proline dehydrogenase (PRODH) may result in structural and functional brain abnormalities and increased vulnerability to schizophrenia as observed in patients with microdeletions of 22q11. Thus, COMT and PRODH could be modifier genes for schizophrenia. We examined association of polymorphisms in COMT and PRODH with brain anatomy in young patients with schizophrenia and schizoaffective disorder. We acquired structural magnetic resonance imaging data from 51 male patients and genotyped two single nucleotide polymorphisms (SNPs) in the COMT gene and three in the PRODH gene. Statistical Parametric Mapping software and optimized voxel-based morphometry were used to determine regional gray matter (GM) and white matter (WM) density differences, and total GM and WM volume differences between genotype groups. Two nonsynonymous SNPs in the PRODH gene were associated with bilateral frontal WM density reductions and an SNP in the P2 promoter region of COMT (rs2097603) was associated with GM increase in the right superior temporal gyrus. Furthermore, we found evidence for COMT and PRODH epistasis: in patients with a COMT Val allele (rs4680) and with one or two mutated PRODH alleles, we observed increased WM density in the left inferior frontal lobe. Our results suggest that genetic variation in COMT and PRODH has significant effects on brain regions known to be affected in schizophrenia. Further research is needed to investigate the role of 22q11 genes on brain structure and function and their role in vulnerability for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 46 | PLoS Genet. 2008 Nov 4: e1000252 |
| PMID | 18989458 |
| Title | Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function. |
| Abstract | PRODH, encoding proline oxidase (POX), has been associated with schizophrenia through linkage, association, and the 22q11 deletion syndrome (Velo-Cardio-Facial syndrome). Here, we show in a family-based sample that functional polymorphisms in PRODH are associated with schizophrenia, with protective and risk alleles having opposite effects on POX activity. Using a multimodal imaging genetics approach, we demonstrate that haplotypes constructed from these risk and protective functional polymorphisms have dissociable correlations with structure, function, and connectivity of striatum and prefrontal cortex, impacting critical circuitry implicated in the pathophysiology of schizophrenia. Specifically, the schizophrenia risk haplotype was associated with decreased striatal volume and increased striatal-frontal functional connectivity, while the protective haplotype was associated with decreased striatal-frontal functional connectivity. Our findings suggest a role for functional genetic variation in POX on neostriatal-frontal circuits mediating risk and protection for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 47 | Amino Acids 2008 Nov 35: 673-9 |
| PMID | 18528746 |
| Title | PRODH variants and risk for schizophrenia. |
| Abstract | schizophrenia is a common, devastating neuropsychiatric disorder whose etiology is largely unknown. Multiple studies in humans and in mouse and fly models suggest a role for proline and PRODH, the gene encoding the first enzyme in the pathway of proline catabolism, in contributing risk for schizophrenia. Other studies, however, reach contradictory conclusions. Here, we provide a critical review of the data in the context of what is known about proline metabolism and suggest studies for the future. Overall, there is considerable evidence supporting a role for certain loss of function PRODH variants conferring risk for schizophrenia in some individuals. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 48 | Brain Struct Funct 2008 Sep 213: 255-71 |
| PMID | 18470533 |
| Title | Age-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex. |
| Abstract | The molecular basis of complex neuropsychiatric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizophrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann's area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18-67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes during the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. All microarray data are available at NCBI's Gene Expression Omnibus: GEO Series accession number GSE11546 (http://www.ncbi.nlm.nih.gov/geo) [corrected] |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 49 | J. Nutr. 2008 Oct 138: 2016S-2020S |
| PMID | 18806117 |
| Title | Inborn errors of proline metabolism. |
| Abstract | l-Proline concentration is primarily related to the balance of enzymatic activities of proline dehydrogenase [proline oxidase (POX)] and Delta-1-pyrroline-5-carboxylate (P5C) reductase. As a result, P5C plays a pivotal role in maintaining the concentration of proline in body fluids and inborn errors of P5C metabolism lead to disturbance of proline metabolism. Several inborn errors of proline metabolism have been described. Hyperprolinemia type I (HPI) is a result of a deficiency in POX. The POX gene (PRODH) is located on chromosome 22 (22q11.2) and this region is deleted in velo-cardio-facial syndrome, a congenital malformation syndrome. In addition, this gene locus is related to susceptibility to schizophrenia. The other type of hyperprolinemia is HPII. It is caused by a deficiency in P5C dehydrogenase activity. Hypoprolinemia, on the other hand, is found in the recently described deficiency of P5C synthetase. This enzyme defect leads to hyperammonemia associated with hypoornithinemia, hypocitrullinemia, and hypoargininemia other than hypoprolinemia. Hyperhydroxyprolinemia is an autosomal recessive inheritance disorder caused by the deficiency of hydroxyproline oxidase. There are no symptoms and it is believed to be a benign metabolic disorder. The deficiency of ornithine aminotransferase causes transient hyperammonemia during early infancy due to deficiency of ornithine in the urea cycle. In later life, gyrate atrophy of the retina occurs due to hyperornithinemia, a paradoxical phenomenon. Finally, prolidase deficiency is a rare autosomal recessive hereditary disease. Prolidase catalyzes hydrolysis of dipeptide or oligopeptide with a C-terminal proline or hydroxyproline and its deficiency can cause mental retardation and severe skin ulcers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 50 | Biol. Psychiatry 2009 Jun 65: 1063-70 |
| PMID | 19232576 |
| Title | A risk PRODH haplotype affects sensorimotor gating, memory, schizotypy, and anxiety in healthy male subjects. |
| Abstract | Significant associations have been shown for haplotypes comprising three PRODH single nucleotide polymorphisms (SNPs; 1945T/C, 1766A/G, 1852G/A) located in the 3' region of the gene, suggesting a role of these variants in the etiopathogenesis of schizophrenia. We assessed the relationship between these high-risk PRODH polymorphisms and schizophrenia-related endophenotypes in a large and highly homogeneous cohort of healthy males. Participants (n = 217) were tested in prepulse inhibition (PPI), verbal and working memory, trait anxiety and schizotypy. The QTPHASE from the UNPHASED package was used for the association analysis of each SNP or haplotype data. This procedure revealed significant phenotypic impact of the risk CGA haplotype. Subjects were then divided in two groups; levels of PPI, anxiety, and schizotypy, verbal and working memory were compared with analysis of variance. CGA carriers (n = 32) exhibited attenuated PPI (p < .001) and verbal memory (p < .001) and higher anxiety (p < .004) and schizotypy (p < .008) compared with the noncarriers (n = 185). There were no differences in baseline startle, demographics, and working memory. The main significant correlations were schizotypy x PPI [85-dB, 120-msec trials] in the carriers and schizotypy x anxiety in the entire group and the noncarriers but not the carriers group. Our results strongly support PPI as a valid schizophrenia endophenotype and highlight the importance of examining the role of risk haplotypes on multiple endophenotypes and have implications for understanding the continuum from normality to psychosis, transitional states, and the genetics of schizophrenia-related traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 51 | Biol. Psychiatry 2009 Jun 65: 1063-70 |
| PMID | 19232576 |
| Title | A risk PRODH haplotype affects sensorimotor gating, memory, schizotypy, and anxiety in healthy male subjects. |
| Abstract | Significant associations have been shown for haplotypes comprising three PRODH single nucleotide polymorphisms (SNPs; 1945T/C, 1766A/G, 1852G/A) located in the 3' region of the gene, suggesting a role of these variants in the etiopathogenesis of schizophrenia. We assessed the relationship between these high-risk PRODH polymorphisms and schizophrenia-related endophenotypes in a large and highly homogeneous cohort of healthy males. Participants (n = 217) were tested in prepulse inhibition (PPI), verbal and working memory, trait anxiety and schizotypy. The QTPHASE from the UNPHASED package was used for the association analysis of each SNP or haplotype data. This procedure revealed significant phenotypic impact of the risk CGA haplotype. Subjects were then divided in two groups; levels of PPI, anxiety, and schizotypy, verbal and working memory were compared with analysis of variance. CGA carriers (n = 32) exhibited attenuated PPI (p < .001) and verbal memory (p < .001) and higher anxiety (p < .004) and schizotypy (p < .008) compared with the noncarriers (n = 185). There were no differences in baseline startle, demographics, and working memory. The main significant correlations were schizotypy x PPI [85-dB, 120-msec trials] in the carriers and schizotypy x anxiety in the entire group and the noncarriers but not the carriers group. Our results strongly support PPI as a valid schizophrenia endophenotype and highlight the importance of examining the role of risk haplotypes on multiple endophenotypes and have implications for understanding the continuum from normality to psychosis, transitional states, and the genetics of schizophrenia-related traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 52 | Proc. Natl. Acad. Sci. U.S.A. 2009 Sep 106: 16434-45 |
| PMID | 19805316 |
| Title | Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome. |
| Abstract | The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5- to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for "diseases of cortical connectivity" thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.5-megabase 22q11 minimal critical deleted region in a mouse model of 22q11DS specifically compromises neurogenesis and subsequent differentiation in the cerebral cortex. Proliferation of basal, but not apical, progenitors is disrupted, and subsequently, the frequency of layer 2/3, but not layer 5/6, projection neurons is altered. This change is paralleled by aberrant distribution of parvalbumin-labeled interneurons in upper and lower cortical layers. Deletion of Tbx1 or PRODH (22q11 genes independently associated with 22q11DS phenotypes) does not similarly disrupt basal progenitors. However, expression analysis implicates additional 22q11 genes that are selectively expressed in cortical precursors. Thus, diminished 22q11 gene dosage disrupts cortical neurogenesis and interneuron migration. Such developmental disruption may alter cortical circuitry and establish vulnerability for developmental disorders, including schizophrenia and autism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 53 | Arch. Gen. Psychiatry 2009 Sep 66: 947-56 |
| PMID | 19736351 |
| Title | Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. |
| Abstract | Results of comparative genomic hybridization studies have suggested that rare copy number variations (CNVs) at numerous loci are involved in the cause of mental retardation, autism spectrum disorders, and schizophrenia. To provide an estimate of the collective frequency of a set of recurrent or overlapping CNVs in 3 different groups of cases compared with healthy control subjects and to assess whether each CNV is present in more than 1 clinical category. Case-control study. Academic research. We investigated 28 candidate loci previously identified by comparative genomic hybridization studies for gene dosage alteration in 247 cases with mental retardation, in 260 cases with autism spectrum disorders, in 236 cases with schizophrenia or schizoaffective disorder, and in 236 controls. Collective and individual frequencies of the analyzed CNVs in cases compared with controls. Recurrent or overlapping CNVs were found in cases at 39.3% of the selected loci. The collective frequency of CNVs at these loci is significantly increased in cases with autism, in cases with schizophrenia, and in cases with mental retardation compared with controls (P < .001, P = .01, and P = .001, respectively, Fisher exact test). Individual significance (P = .02 without correction for multiple testing) was reached for the association between autism and a 350-kilobase deletion located at 22q11 and spanning the PRODH and DGCR6 genes. Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs (which contain genes involved in neurotransmission or in synapse formation and maintenance) are present in the 3 pathologic conditions (schizophrenia, autism, and mental retardation), supporting the existence of shared biologic pathways in these neurodevelopmental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 54 | PLoS ONE 2011 -1 6: e21685 |
| PMID | 21738766 |
| Title | Proton magnetic resonance spectroscopy in 22q11 deletion syndrome. |
| Abstract | People with velo-cardio-facial syndrome or 22q11 deletion syndrome (22q11DS) have behavioral, cognitive and psychiatric problems. Approximately 30% of affected individuals develop schizophrenia-like psychosis. Glutamate dysfunction is thought to play a crucial role in schizophrenia. However, it is unknown if and how the glutamate system is altered in 22q11DS. People with 22q11DS are vulnerable for haploinsufficiency of PRODH, a gene that codes for an enzyme converting proline into glutamate. Therefore, it can be hypothesized that glutamatergic abnormalities may be present in 22q11DS. We employed proton magnetic resonance spectroscopy ((1)H-MRS) to quantify glutamate and other neurometabolites in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of 22 adults with 22q11DS (22q11DS SCZ+) and without (22q11DS SCZ-) schizophrenia and 23 age-matched healthy controls. Also, plasma proline levels were determined in the 22q11DS group. We found significantly increased concentrations of glutamate and myo-inositol in the hippocampal region of 22q11DS SCZ+ compared to 22q11DS SCZ-. There were no significant differences in levels of plasma proline between 22q11DS SCZ+ and 22q11DS SCZ-. There was no relationship between plasma proline and cerebral glutamate in 22q11DS. This is the first in vivo(1)H-MRS study in 22q11DS. Our results suggest vulnerability of the hippocampus in the psychopathology of 22q11DS SCZ+. Altered hippocampal glutamate and myo-inositol metabolism may partially explain the psychotic symptoms and cognitive impairments seen in this group of patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 55 | Schizophr. Res. 2011 Sep 131: 139-45 |
| PMID | 21645996 |
| Title | Evidence for association of hyperprolinemia with schizophrenia and a measure of clinical outcome. |
| Abstract | There are multiple genetic links between schizophrenia and a deficit of proline dehydrogenase (PRODH) enzyme activity. However, reports testing for an association of schizophrenia with the resulting proline elevation have been conflicting. The objectives of this study were to investigate whether hyperprolinemia is associated with schizophrenia, and to measure the relationship between plasma proline, and clinical features and symptoms of schizophrenia. We performed a cross-sectional case-control study, comparing fasting plasma proline in 90 control subjects and 64 schizophrenic patients and testing for association of mild to moderate hyperprolinemia with schizophrenia. As secondary analyses, the relationship between hyperprolinemia and five measures of clinical onset, symptoms and outcome were investigated. Patients had significantly higher plasma proline than matched controls (p<0.0001), and categorical analysis of gender adjusted hyperprolinemia showed a significant association with schizophrenia (OR 6.15, p=0.0003). Hyperprolinemic patients were significantly older at their first hospitalization (p=0.015 following correction for multiple testing). While plasma proline level was not related to total, positive or negative symptoms, hyperprolinemic status had a significant effect on length of hospital stay (p=0.005), following adjustment for race, BPRS score, and cross-sectional time from admission to proline measurement. Mild to moderate hyperprolinemia is a significant risk factor for schizophrenia, and may represent an intermediate phenotype in the disease. Hyperprolinemic patients have a significantly later age of first psychiatric hospitalization, suggestive of later onset, and hospital stays 46% longer than non-hyperprolinemic subjects. These findings have implications in the etiology of schizophrenia, and for the clinical management of these patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 56 | Schizophr. Res. 2011 Sep 131: 139-45 |
| PMID | 21645996 |
| Title | Evidence for association of hyperprolinemia with schizophrenia and a measure of clinical outcome. |
| Abstract | There are multiple genetic links between schizophrenia and a deficit of proline dehydrogenase (PRODH) enzyme activity. However, reports testing for an association of schizophrenia with the resulting proline elevation have been conflicting. The objectives of this study were to investigate whether hyperprolinemia is associated with schizophrenia, and to measure the relationship between plasma proline, and clinical features and symptoms of schizophrenia. We performed a cross-sectional case-control study, comparing fasting plasma proline in 90 control subjects and 64 schizophrenic patients and testing for association of mild to moderate hyperprolinemia with schizophrenia. As secondary analyses, the relationship between hyperprolinemia and five measures of clinical onset, symptoms and outcome were investigated. Patients had significantly higher plasma proline than matched controls (p<0.0001), and categorical analysis of gender adjusted hyperprolinemia showed a significant association with schizophrenia (OR 6.15, p=0.0003). Hyperprolinemic patients were significantly older at their first hospitalization (p=0.015 following correction for multiple testing). While plasma proline level was not related to total, positive or negative symptoms, hyperprolinemic status had a significant effect on length of hospital stay (p=0.005), following adjustment for race, BPRS score, and cross-sectional time from admission to proline measurement. Mild to moderate hyperprolinemia is a significant risk factor for schizophrenia, and may represent an intermediate phenotype in the disease. Hyperprolinemic patients have a significantly later age of first psychiatric hospitalization, suggestive of later onset, and hospital stays 46% longer than non-hyperprolinemic subjects. These findings have implications in the etiology of schizophrenia, and for the clinical management of these patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 57 | Curr Top Med Chem 2012 -1 12: 2303-13 |
| PMID | 23279171 |
| Title | Neuroimaging correlates of 22q11.2 deletion syndrome: implications for schizophrenia research. |
| Abstract | 22q11.2 Deletion syndrome (22q11DS) is the most common known recurrent copy-number variant disorder. It is also the most common known genetic risk factor for schizophrenia. The greater homogeneity of subjects with schizophrenia in 22q11DS compared with schizophrenia in the wider non-deleted population may help to identify much needed information on neuroanatomical substrates, and neurochemical and neurofunctional mechanisms that may modulate the risk for schizophrenia. Identification of the underlying pathophysiology creates opportunities for developing genotype-specific, biology-based and targeted treatments to prevent, delay or minimize the severity of schizophrenia in both 22q11DS and the wider non-deleted population. This article reviews neuroimaging studies that focused on brain structure and function in this high-risk population, with particular attention to schizophrenia research. We also discuss the evidence on the role of candidate genes within the 22q11.2 region, with particular reference to catechol-O-methyl transferase (COMT) and proline dehydrogenase (PRODH). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 58 | Neuropharmacology 2012 Mar 62: 1204-20 |
| PMID | 21557953 |
| Title | Mouse models of genetic effects on cognition: relevance to schizophrenia. |
| Abstract | Cognitive dysfunction is a core feature of schizophrenia. Growing evidence indicates that a wide variety of genetic mutations and polymorphisms impact cognition and may thus be implicated in various aspects of this mental disorder. Despite differences between human and rodent brain structure and function, genetic mouse models have contributed critical information about brain mechanisms involved in cognitive processes. Here, we summarize discoveries of genetic modifications in mice that impact cognition. Based on functional hypotheses, gene modifications within five model systems are described: 1) dopamine (D1, D2, D3, D4, D5, DAT, COMT, MAO); 2) glutamate (GluR-A, NR1, NR2A, NR2B, GRM2, GRM3, GLAST); 3) GABA (?(5), ?(2), ?(4), ?GABA(A), GABA(B(1)), GAT1); 4) acetylcholine (nAChR?2, ?7, CHRM1); and 5) calcium (CaMKII-?, neurogranin, CaMKK?, CaMKIV). We also consider other risk-associated genes for schizophrenia such as dysbindin (DTNBP1), neuregulin (NRG1), disrupted-in-schizophrenia1 (DISC1), reelin and proline dehydrogenase (PRODH). Because of the presumed importance of environmental factors, we further consider genetic modifications within the stress-sensitive systems of corticotropin-releasing factor (CRF), brain-derived neurotrophic factor (BDNF) and the endocannabinoid systems. We highlight the missing information and limitations of cognitive assays in genetically modified mice models relevant to schizophrenia pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 59 | Protein Expr. Purif. 2012 Apr 82: 345-51 |
| PMID | 22333530 |
| Title | Expression in Escherichia coli of the catalytic domain of human proline oxidase. |
| Abstract | The human PRODH gene has been shown to have unique roles in regulating cell survival and apoptotic pathways and it has been related to velocardiofacial syndrome/DiGeorge syndrome and increased susceptibility to schizophrenia. It encodes for the flavoprotein proline oxidase (PO), which catalyzes the conversion of l-proline to ?(1)-pyrroline-5-carboxylate. Despite the important physiological and medical interest in human PO, up to now only microbial homologues of PO have been expressed as recombinant protein and fully characterized. By using a bioinformatics analysis aimed at identifying the catalytic domain and the regions with a high intrinsic propensity to structural disorder, we designed deletion variants of human PO that were successfully expressed in Escherichia coli as soluble proteins in fairly high amounts (up to 10mg/L of fermentation broth). The His-tagged PO-barrelN protein was isolated as an active (the specific activity is 0.032U/mg protein), dimeric holoenzyme showing the typical spectral properties of FAD-containing flavoprotein oxidases. These results pave the way for elucidating structure-function relationships of this human flavoenzyme and clarifying the effect of the reported polymorphisms associated with disease states. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 60 | Int. J. Neuropsychopharmacol. 2012 May 15: 459-69 |
| PMID | 21682944 |
| Title | DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population. |
| Abstract | It is well accepted that schizophrenia has a strong genetic component. Several genome-wide association studies (GWASs) of schizophrenia have been published in recent years; most of them population based with a case-control design. Nevertheless, identifying the specific genetic variants which contribute to susceptibility to the disorder remains a challenging task. A family-based GWAS strategy may be helpful in the identification of schizophrenia susceptibility genes since it is protected against population stratification, enables better accounting for genotyping errors and is more sensitive for identification of rare variants which have a very low frequency in the general population. In this project we implemented a family-based GWAS of schizophrenia in a sample of 107 Jewish-Israeli families. We found one genome-wide significant association in the intron of the DOCK4 gene (rs2074127, p value=1.134×10??) and six additional nominally significant association signals with p<1×10??. One of the top single nucleotide polymorphisms (p<1×10??) which is located in the predicted intron of the CEACAM21 gene was significantly replicated in independent family-based sample of Arab-Israeli origin (rs4803480: p value=0.002; combined p value=9.61×10??), surviving correction for multiple testing. Both DOCK4 and CEACAM21 are biologically reasonable candidate genes for schizophrenia although generalizability of the association of DOCK4 with schizophrenia should be investigated in further studies. In addition, gene-wide significant associations were found within three schizophrenia candidate genes: PGBD1, RELN and PRODH, replicating previously reported associations. By application of a family-based strategy to GWAS, our study revealed new schizophrenia susceptibility loci in the Jewish-Israeli population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 61 | World J Psychiatry 2013 Sep 3: 57-61 |
| PMID | 24255876 |
| Title | New findings in the genetics of schizophrenia. |
| Abstract | New findings in schizophrenia genetics are based on genome-wide association studies (GWAS), research into DNA copy number variations (CNVs), and endophenotypes. More than 70 genes have recently been suspected to be involved in the genetic background of schizophrenia based on the GWAS´s results. They are typically related to neurodevelopment/neuroplasticity, immunology and neuroendocrinology. Nevertheless, for many detected genes their possible relationship to schizophrenia etiopathogenesis is still unknown. The CNVs at genome loci 1q21.1 (candidate gene e.g., PRKAB2), 2p16.3 (candidate gene e.g., NRXN1), 3q29 (candidate genes e.g., BDH1, DLG1, PAK2 or TFRC), 15q11.2 (candidate gene e.g., CYFIP1), 15q13.3 (candidate gene e.g., CHRNA7), 16p13.1 (candidate genes e.g.,NTAN1 or NDE1) and 22q11.2 (candidate genes e.g., COMT, GSTT2 or PRODH) were associated with schizophrenia most frequently. Genetic research of schizophrenia endophenotypes, usually neurophysiological, neuromotoric, neurocognitive, neuroanatomical, neurological or personality-related, will help us to discover the role of relevant genes in the pathogenesis of schizophrenia. It is also necessary to integrate knowledge from other research platforms in schizophrenia, like epigenetics, studies of gene-environment interactions, transcriptomics, proteomics, metabolomics, neuroimaging and psychopathology. A better knowledge of the genetic background of schizophrenia can lead to changes in the treatment, prevention and genetic counselling. It may also reduce stigma in this severe mental disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 62 | Proc. Natl. Acad. Sci. U.S.A. 2013 Nov 110: 19472-7 |
| PMID | 24218577 |
| Title | Human-specific endogenous retroviral insert serves as an enhancer for the schizophrenia-linked gene PRODH. |
| Abstract | Using a systematic, whole-genome analysis of enhancer activity of human-specific endogenous retroviral inserts (hsERVs), we identified an element, hsERVPRODH, that acts as a tissue-specific enhancer for the PRODH gene, which is required for proper CNS functioning. PRODH is one of the candidate genes for susceptibility to schizophrenia and other neurological disorders. It codes for a proline dehydrogenase enzyme, which catalyses the first step of proline catabolism and most likely is involved in neuromediator synthesis in the CNS. We investigated the mechanisms that regulate hsERVPRODH enhancer activity. We showed that the hsERVPRODH enhancer and the internal CpG island of PRODH synergistically activate its promoter. The enhancer activity of hsERVPRODH is regulated by methylation, and in an undermethylated state it can up-regulate PRODH expression in the hippocampus. The mechanism of hsERVPRODH enhancer activity involves the binding of the transcription factor SOX2, whch is preferentially expressed in hippocampus. We propose that the interaction of hsERVPRODH and PRODH may have contributed to human CNS evolution. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 63 | J Psychiatr Res 2013 Nov 47: 1623-9 |
| PMID | 23910792 |
| Title | Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes. |
| Abstract | 22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia - P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val(158)Met (rs4680) and PRODH Gln(19)Pro (rs2008720) and Arg(185)Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 64 | Psychiatr. Genet. 2014 Dec 24: 269-72 |
| PMID | 25325218 |
| Title | Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes. |
| Abstract | Velocardiofacial (VCFS; 22q11.2 deletion) syndrome is a genetic disorder that results from a hemizygous deletion of the q11.2 region on chromosome 22, and is associated with greatly increased risk for psychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. There is emerging evidence for the involvement of catechol-O-methyltransferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH) in the psychiatric phenotype of individuals with VCFS. Here, we tested the hypothesis that PRODH and COMT are associated with ASD in youths with VCFS. We found that individuals with VCFS and the low-activity alleles of both PRODH and COMT (rs4819756A and rs4680A) were more likely to present with ASD as compared with individuals with VCFS and the high-activity alleles of these genes [P<0.05; odds ratio=6.0 (95% confidence interval=1.27-28.26; N=87)]. Our results suggest that PRODH and COMT may interact to contribute to the ASD phenotype in individuals with VCFS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 65 | J Psychiatr Res 2014 Sep 56: 28-35 |
| PMID | 24853458 |
| Title | Association of COMT and PRODH gene variants with intelligence quotient (IQ) and executive functions in 22q11.2DS subjects. |
| Abstract | The 22q11.2 deletion syndrome (22q11.2DS) carries the highest genetic risk factor for the development of schizophrenia. We investigated the association of genetic variants in two schizophrenia candidate genes with executive function (EF) and IQ in 22q11.2DS individuals. Ninety two individuals with 22q11.2 deletion were studied for the genetic association between COMT and PRODH variants and EF and IQ. Subjects were divided into children (under 12 years old), adolescents (between 12 and 18 years old) and adults (older than 18 years), and genotyped for the COMT Val158Met (rs4680) and PRODH Arg185Trp (rs4819756) polymorphisms. The participants underwent psychiatric evaluation and EF assessment. Our main finding is a significant influence of the COMT Val158Met polymorphism on both IQ and EF performance. Specifically, 22q11.2DS subjects with Met allele displayed higher IQ scores in all age groups compared to Val carriers, reaching significance in both adolescents and adults. The Met allele carriers performed better than Val carriers in EF tasks, being statistically significant in the adult group. PRODH Arg185Trp variant did not affect IQ or EF in our 22q11.2DS cohort. In conclusion, functional COMT variant, but not PRODH, affects IQ and EF in 22q11.2DS subjects during neurodevelopment with a maximal effect at adulthood. Future studies should monitor the cognitive performance of the same individuals from childhood to old age. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 66 | Seishin Shinkeigaku Zasshi 2014 -1 116: 842-58 |
| PMID | 25672211 |
| Title | [Role of oxidative stress in the pathophysiology of neuropsychiatric disorders]. |
| Abstract | The brain is particularly vulnerable to oxidative damage because of its high rate of oxygen consumption, abundant lipid content, and relative paucity of antioxidant enzymes compared with other organs. It has been well established that oxidative stress (OS) is involved in the pathogenesis of age-associated neurodegenerative disorders such as Alzheimer's disease (AD). Indeed, a large number of genetic and environmental factors of neurodegenerative disorders are associated with OS. Of note, studies on the levels of oxidative damage in patients with the prodromal stage of AD, transgenic animal models of AD, and induced pluripotent stem (iPS) cells derived from AD patients support the early-stage involvement of OS in the pathological cascade of the disorder. Recently, a growing body of evidence suggests that a considerable number of genetic and environmental factors of psychiatric disorders such as schizophrenia (SZ), bipolar disorders, and depression are associated with OS. Not only genetic polymorphisms in genes encoding antioxidant enzymes but also several known susceptible genes for psychiatric disorders, i. e., Disrupted-in-schizophrenia-1 (DISC1), Neuregulin 1 (NRG1), proline dehydrogenase (PRODH), and G72, are all associated with increased levels of OS or decreased antioxidant capacities. Moreover, environmental factors such as infection, hypoxia, malnutrition, illicit substance use, and psychosocial stress are possibly associated with OS. In fact, increased levels of oxidized nucleic acids, proteins, and lipids have been described in the postmortem brains of patients with SZ and bipolar disorders, and decreased antioxidant capacities have been described in blood samples obtained from patients with first-episode psychosis. In concordance, iPS cells from SZ patients show an increased level of OS. Of particular interest is a conditional gene knockout mouse model of SZ with the functional elimination of NMDA receptors specifically from cortical interneurons. The NMDA receptor knockout mouse shows behavioral phenotypes resembling symptoms of human SZ. Importantly, a marked increase of OS, particularly in the cortical parvalbumin-positive interneurons, is rapidly exacerbated by post-weaning social isolation, but treatment with antioxidants abolishes OS and partially alleviates the SZ-like behavioral phenotypes. Therefore, it is suggested that OS is a convergence point for genetic and environmental susceptibilities to not only neurodegenerative but also psychiatric disorders. In other words, OS potentially plays a central role in the pathomechanisms that integrate gene-environment interactions in neuropsychiatric disorders. Further investigations into the development of useful OS biomarkers and efficacious OS-targeting interventions may shed light on a promising approach for establishing preemptive strategies against neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 67 | Schizophr. Res. 2014 Jun 156: 15-22 |
| PMID | 24787057 |
| Title | Vitamin D insufficiency and schizophrenia risk: evaluation of hyperprolinemia as a mediator of association. |
| Abstract | 25-Hydroxyvitamin D (25(OH)D) deficits have been associated with schizophrenia susceptibility and supplementation has been recommended for those at-risk. Although the mechanism by which a deficit confers risk is unknown, vitamin D is a potent transcriptional modulator and can regulate proline dehydrogenase (PRODH) expression. PRODH maps to chromosome 22q11, a region conferring the highest known genetic risk of schizophrenia, and encodes proline oxidase, which catalyzes proline catabolism. l-Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with decreased IQ, cognitive impairment, schizoaffective disorder, and schizophrenia. We investigated the relationship between 25(OH)D and schizophrenia, comparing fasting plasma 25(OH)D in 64 patients and 90 matched controls. We then tested for a mediating effect of hyperprolinemia on the association between 25(OH)D and schizophrenia. 25(OH)D levels were significantly lower in patients, and 25(OH)D insufficiency associated with schizophrenia (OR 2.1, adjusted p=0.044, 95% CI: 1.02-4.46). Moreover, 25(OH)D insufficient subjects had three times greater odds of hyperprolinemia than those with optimal levels (p=0.035, 95% CI: 1.08-8.91), and formal testing established that hyperprolinemia is a significantly mediating phenotype that may explain over a third of the effect of 25(OH)D insufficiency on schizophrenia risk. This study presents a mechanism by which 25(OH)D insufficiency confers risk of schizophrenia; via proline elevation due to reduced PRODH expression, and a concomitant dysregulation of neurotransmission. Although definitive causality cannot be confirmed, these findings strongly support vitamin D supplementation in patients, particularly for those with elevated proline, who may represent a large subgroup of the schizophrenia population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 68 | PLoS ONE 2014 -1 9: e87686 |
| PMID | 24498354 |
| Title | PRODH polymorphisms, cortical volumes and thickness in schizophrenia. |
| Abstract | schizophrenia is a neurodevelopmental disorder with high heritability. Several lines of evidence indicate that the PRODH gene may be related to the disorder. Therefore, our study investigates the effects of 12 polymorphisms of PRODH on schizophrenia and its phenotypes. To further evaluate the roles of the associated variants in the disorder, we have conducted magnetic resonance imaging (MRI) scans to assess cortical volumes and thicknesses. A total of 192 patients were evaluated using the Structured Clinical Interview for DSM-IV (SCID), Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) instruments. The study included 179 controls paired by age and gender. The samples were genotyped using the real-time polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP)-PCR and Sanger sequencing methods. A sample of 138 patients and 34 healthy controls underwent MRI scans. One polymorphism was associated with schizophrenia (rs2904552), with the G-allele more frequent in patients than in controls. This polymorphism is likely functional, as predicted by PolyPhen and SIFT, but it was not associated with brain morphology in our study. In summary, we report a functional PRODH variant associated with schizophrenia that may have a neurochemical impact, altering brain function, but is not responsible for the cortical reductions found in the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 69 | J. Biol. Chem. 2015 Sep 290: 23240-53 |
| PMID | 26221035 |
| Title | Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome. |
| Abstract | The congenital disorder 22q11.2 deletion syndrome (22qDS), characterized by a hemizygous deletion of 1.5-3 Mb on chromosome 22 at locus 11.2, is the most common microdeletion disorder (estimated prevalence of 1 in 4000) and the second risk factor for schizophrenia. Nine of ?30 genes involved in 22qDS have the potential of disrupting mitochondrial metabolism (COMT, UFD1L, DGCR8, MRPL40, PRODH, SLC25A1, TXNRD2, T10, and ZDHHC8). Deficits in bioenergetics during early postnatal brain development could set the basis for a disrupted neuronal metabolism or synaptic signaling, partly explaining the higher incidence in developmental and behavioral deficits in these individuals. Here, we investigated whether mitochondrial outcomes and metabolites from 22qDS children segregated with the altered dosage of one or several of these mitochondrial genes contributing to 22qDS etiology and/or morbidity. Plasma metabolomics, lymphocytic mitochondrial outcomes, and epigenetics (histone H3 Lys-4 trimethylation and 5-methylcytosine) were evaluated in samples from 11 22qDS children and 13 age- and sex-matched neurotypically developing controls. Metabolite differences between 22qDS children and controls reflected a shift from oxidative phosphorylation to glycolysis (higher lactate/pyruvate ratios) accompanied by an increase in reductive carboxylation of ?-ketoglutarate (increased concentrations of 2-hydroxyglutaric acid, cholesterol, and fatty acids). Altered metabolism in 22qDS reflected a critical role for the haploinsufficiency of the mitochondrial citrate transporter SLC25A1, further enhanced by HIF-1?, MYC, and metabolite controls. This comprehensive profiling served to clarify the biochemistry of this disease underlying its broad, complex phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 70 | Genet. Mol. Res. 2015 -1 14: 11681-91 |
| PMID | 26436492 |
| Title | Relationship between polymorphisms in the proline dehydrogenase gene and schizophrenia risk. |
| Abstract | Previous studies have suggested that an association exists between the proline dehydrogenase gene (PRODH) and increased schizophrenia risk. We examined the prevalence of the PRODH 757C/T (Arg185Trp), 1766A/G (Gly521Arg), and 1852G/A (intronic mutation) polymorphisms in 175 patients with schizophrenia and 185 control subjects. All subjects were of Iranian ancestry. The PRODH 757TT, 1852AA, and 1766GG genotypes were associated with an increased risk of schizophrenia (odds ratio = 1.38, 95% confidence interval: 0.88-2.16, P = 0.001, P = 0.001, respectively). The activity alleles in the PRODH genotype combinations were associated with an increased risk of schizophrenia (haplotype analysis, TAG genotype P = 0.007). Our findings support a major role for the PRODH 757TT, 1766GG, and 1852AA genotypes alone and in combination for schizophrenia susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 71 | Hum. Mutat. 2015 Aug 36: 797-807 |
| PMID | 25981510 |
| Title | Whole-Genome Sequencing and Integrative Genomic Analysis Approach on Two 22q11.2 Deletion Syndrome Family Trios for Genotype to Phenotype Correlations. |
| Abstract | The 22q11.2 deletion syndrome (22q11DS) affects 1:4,000 live births and presents with highly variable phenotype expressivity. In this study, we developed an analytical approach utilizing whole-genome sequencing (WGS) and integrative analysis to discover genetic modifiers. Our pipeline combined available tools in order to prioritize rare, predicted deleterious, coding and noncoding single-nucleotide variants (SNVs), and insertion/deletions from WGS. We sequenced two unrelated probands with 22q11DS, with contrasting clinical findings, and their unaffected parents. Proband P1 had cognitive impairment, psychotic episodes, anxiety, and tetralogy of Fallot (TOF), whereas proband P2 had juvenile rheumatoid arthritis but no other major clinical findings. In P1, we identified common variants in COMT and PRODH on 22q11.2 as well as rare potentially deleterious DNA variants in other behavioral/neurocognitive genes. We also identified a de novo SNV in ADNP2 (NM_014913.3:c.2243G>C), encoding a neuroprotective protein that may be involved in behavioral disorders. In P2, we identified a novel nonsynonymous SNV in ZFPM2 (NM_012082.3:c.1576C>T), a known causative gene for TOF, which may act as a protective variant downstream of TBX1, haploinsufficiency of which is responsible for congenital heart disease in individuals with 22q11DS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 72 | Mol. Psychiatry 2015 Dec 20: 1557-64 |
| PMID | 25666758 |
| Title | Genome-wide association study of NMDA receptor coagonists in human cerebrospinal fluid and plasma. |
| Abstract | The N-methyl-D-aspartate receptor (NMDAR) coagonists glycine, D-serine and L-proline play crucial roles in NMDAR-dependent neurotransmission and are associated with a range of neuropsychiatric disorders. We conducted the first genome-wide association study of concentrations of these coagonists and their enantiomers in plasma and cerebrospinal fluid (CSF) of human subjects from the general population (N=414). Genetic variants at chromosome 22q11.2, located in and near PRODH (proline dehydrogenase), were associated with L-proline in plasma (?=0.29; P=6.38 × 10(-10)). The missense variant rs17279437 in the proline transporter SLC6A20 was associated with L-proline in CSF (?=0.28; P=9.68 × 10(-9)). Suggestive evidence of association was found for the D-serine plasma-CSF ratio at the D-amino-acid oxidase (DAO) gene (?=-0.28; P=9.08 × 10(-8)), whereas a variant in SRR (that encodes serine racemase and is associated with schizophrenia) constituted the most strongly associated locus for the L-serine to D-serine ratio in CSF. All these genes are highly expressed in rodent meninges and choroid plexus, anatomical regions relevant to CSF physiology. The enzymes and transporters they encode may be targeted to further construe the nature of NMDAR coagonist involvement in NMDAR gating. Furthermore, the highlighted genetic variants may be followed up in clinical populations, for example, schizophrenia and 22q11 deletion syndrome. Overall, this targeted metabolomics approach furthers the understanding of NMDAR coagonist concentration variability and sets the stage for non-targeted CSF metabolomics projects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 73 | J Neurodev Disord 2015 -1 7: 18 |
| PMID | 26137170 |
| Title | Comparative mapping of the 22q11.2 deletion region and the potential of simple model organisms. |
| Abstract | 22q11.2 deletion syndrome (22q11.2DS) is the most common micro-deletion syndrome. The associated 22q11.2 deletion conveys the strongest known molecular risk for schizophrenia. Neurodevelopmental phenotypes, including intellectual disability, are also prominent though variable in severity. Other developmental features include congenital cardiac and craniofacial anomalies. Whereas existing mouse models have been helpful in determining the role of some genes overlapped by the hemizygous 22q11.2 deletion in phenotypic expression, much remains unknown. Simple model organisms remain largely unexploited in exploring these genotype-phenotype relationships. We first developed a comprehensive map of the human 22q11.2 deletion region, delineating gene content, and brain expression. To identify putative orthologs, standard methods were used to interrogate the proteomes of the zebrafish (D. rerio), fruit fly (D. melanogaster), and worm (C. elegans), in addition to the mouse. Spatial locations of conserved homologues were mapped to examine syntenic relationships. We systematically cataloged available knockout and knockdown models of all conserved genes across these organisms, including a comprehensive review of associated phenotypes. There are 90 genes overlapped by the typical 2.5 Mb deletion 22q11.2 region. Of the 46 protein-coding genes, 41 (89.1 %) have documented expression in the human brain. Identified homologues in the zebrafish (n = 37, 80.4 %) were comparable to those in the mouse (n = 40, 86.9 %) and included some conserved gene cluster structures. There were 22 (47.8 %) putative homologues in the fruit fly and 17 (37.0 %) in the worm involving multiple chromosomes. Individual gene knockdown mutants were available for the simple model organisms, but not for mouse. Although phenotypic data were relatively limited for knockout and knockdown models of the 17 genes conserved across all species, there was some evidence for roles in neurodevelopmental phenotypes, including four of the six mitochondrial genes in the 22q11.2 deletion region. Simple model organisms represent a powerful but underutilized means of investigating the molecular mechanisms underlying the elevated risk for neurodevelopmental disorders in 22q11.2DS. This comparative multi-species study provides novel resources and support for the potential utility of non-mouse models in expression studies and high-throughput drug screening. The approach has implications for other recurrent copy number variations associated with neurodevelopmental phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |