Literature Search Results for Gene IMPA2

IMPA2
1
Mol. Psychiatry 2001 Mar 6: 202-10
PMID11317223
TitleEvidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples.
AbstractIn our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase gene, that maps to 18p11.2. We determined its genomic structure and detected three new single nucleotide polymorphisms (SNPs). In the present study, we screened the gene further to search for additional polymorphisms in Japanese samples and identified seven other SNPs, including a novel missense mutation. These polymorphisms clustered into three regions of the gene. Three relatively informative SNPs, 58G>A, IVS1--15G>A and 800C>T from clusters 1, 2 and 3, respectively, were selected for association tests using a case-control design. The Japanese cohort included 302 schizophrenics, 205 patients with affective disorder and 308 controls. Genotyping was done either by melting curve analysis on the LightCycler or by sequencing. All three SNPs showed significant genotypic association (nominal P = 0.031--0.0001) with schizophrenia, but not with affective disorder. These findings increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity to IMPA2. Our findings suggest that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese.
SCZ Keywordsschizophrenia,schizophrenics
2
Mol. Psychiatry 2001 Mar 6: 202-10
PMID11317223
TitleEvidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples.
AbstractIn our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase gene, that maps to 18p11.2. We determined its genomic structure and detected three new single nucleotide polymorphisms (SNPs). In the present study, we screened the gene further to search for additional polymorphisms in Japanese samples and identified seven other SNPs, including a novel missense mutation. These polymorphisms clustered into three regions of the gene. Three relatively informative SNPs, 58G>A, IVS1--15G>A and 800C>T from clusters 1, 2 and 3, respectively, were selected for association tests using a case-control design. The Japanese cohort included 302 schizophrenics, 205 patients with affective disorder and 308 controls. Genotyping was done either by melting curve analysis on the LightCycler or by sequencing. All three SNPs showed significant genotypic association (nominal P = 0.031--0.0001) with schizophrenia, but not with affective disorder. These findings increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity to IMPA2. Our findings suggest that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese.
SCZ Keywordsschizophrenia,schizophrenics
3
J. Med. Dent. Sci. 2003 Sep 50: 225-9
PMID15074360
TitleC18orf1 located on chromosome 18p11.2 may confer susceptibility to schizophrenia.
AbstractThe pericentromeric region of chromosome 18, especially 18p11.2, is described as a schizophrenia susceptibility locus. We had previously cloned two novel brain-derived transcripts from this region: the gene for a second human myo-inositol monophosphatase (IMPA2) and a gene of unknown function, C18orf1. Recently, we reported a distortion of transmission of the tandem repeat marker D18S852, embedded in the 3'-untranslated region of C18orf1, in schizophrenia, using a family-based association test. A subsequent case-control study also revealed a significant association between the haplotype constructed from D18S852 and the 6409T>C polymorphism located in C18orf1 and schizophrenia. In the present study, we screened the C18orf1 gene for mutations and identified a novel single nucleotide polymorphism (SNP), -96T>C in exon 2. This SNP showed significant genotypic (P = 0.048) and allelic association (P = 0.005) with schizophrenia in a case-control study. The distributions of haplotypes defined by D18S852 and -96T>C were different between control and schizophrenia groups (P = 0.021). These findings suggest that C18orf1 or a gene nearby may contribute to the overall genetic risk for schizophrenia.
SCZ Keywordsschizophrenia,schizophrenics
4
Clin Invest Med 2003 Dec 26: 285-302
PMID14690303
TitleGenetic analysis of psychiatric disorders associated with human chromosome 18.
AbstractCurrent models on the etiology of psychiatric disorders support the idea of a biologic cause as well as interactions of biologic systems with the environment. The elucidation of the genetic etiology is of paramount importance to understand the cause of psychiatric disorders. Human chromosome 18 was identified as one of the first chromosomes to be aberrant in psychiatric patients and has subsequently served as a model to identify the molecular cause. In this article I review a multitude of methodologies that can be used in determining the genetic basis of schizophrenia, affective disorder and autism associated with human chromosome 18. These strategies include the use of chromosome aberrations, linkage and association studies, mouse-human comparative genomics, mutation analysis on candidate genes, trinucleotide repeat expansion studies, search for genes demonstrating parental effects and bioinformatics. Current data from the use of these methods are cited from the literature. Linkage and association studies have suggested at least 2 candidate loci on the short and long arms of chromosome 18 for each of these psychiatric disorders. Some loci are supported by the mapping of chromosome aberrations from psychiatric patients. Mutation analyses of psychiatric patients with 4 candidate genes (NEDD4L, IMPA2, PACAP and GNAL) mapping within these loci have been unsuccessful, although an association was found with the IMPA2 gene in patients with schizophrenia. With these methods and findings, our understanding of the cause of psychiatric disorders associated with human chromosome 18 has improved and will advance, especially with emerging data from the human and rodent genome projects.
SCZ Keywordsschizophrenia,schizophrenics
5
Schizophr Bull 2007 Nov 33: 1343-53
PMID17329232
TitleeIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia?
AbstractBipolar disorder and schizophrenia share common chromosomal susceptibility loci and many risk-promoting genes. Oligodendrocyte cell loss and hypomyelination are common to both diseases. A number of environmental risk factors including famine, viral infection, and prenatal or childhood stress may also predispose to schizophrenia or bipolar disorder. In cells, related stressors (starvation, viruses, cytokines, oxidative, and endoplasmic reticulum stress) activate a series of eIF2-alpha kinases, which arrest protein synthesis via the eventual inhibition, by phosphorylated eIF2-alpha, of the translation initiation factor eIF2B. Growth factors increase protein synthesis via eIF2B activation and counterbalance this system. The control of protein synthesis by eIF2-alpha kinases is also engaged by long-term potentiation and repressed by long-term depression, mediated by N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors. Many genes reportedly associated with both schizophrenia and bipolar disorder code for proteins within or associated with this network. These include NMDA (GRIN1, GRIN2A, GRIN2B) and metabotropic (GRM3, GRM4) glutamate receptors, growth factors (BDNF, NRG1), and many of their downstream signaling components or accomplices (AKT1, DAO, DAOA, DISC1, DTNBP1, DPYSL2, IMPA2, NCAM1, NOS1, NOS1AP, PIK3C3, PIP5K2A, PDLIM5, RGS4, YWHAH). They also include multiple gene products related to the control of the stress-responsive eIF2-alpha kinases (IL1B, IL1RN, MTHFR, TNF, ND4, NDUFV2, XBP1). Oligodendrocytes are particularly sensitive to defects in the eIF2B complex, mutations in which are responsible for vanishing white matter disease. The convergence of natural and genetic risk factors on this area in bipolar disorder and schizophrenia may help to explain the apparent vulnerability of this cell type in these conditions. This convergence may also help to reconcile certain arguments related to the importance of nature and nurture in the etiology of these psychiatric disorders. Both may affect common stress-related signaling pathways that dictate oligodendrocyte viability and synaptic plasticity.
SCZ Keywordsschizophrenia,schizophrenics
6
Psychiatry Clin. Neurosci. 2007 Feb 61: 3-19
PMID17239033
TitleMolecular genetics of bipolar disorder and depression.
AbstractIn this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene-environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field.
SCZ Keywordsschizophrenia,schizophrenics
7
Proteins 2007 May 67: 732-42
PMID17340635
TitleCrystal structure of human myo-inositol monophosphatase 2, the product of the putative susceptibility gene for bipolar disorder, schizophrenia, and febrile seizures.
AbstractThe human IMPA2 gene, which encodes myo-inositol monophosphatase 2 (IMPA2), is mapped onto 18p11.2, a susceptibility region for bipolar disorder. This chromosomal region has also been proposed to include a susceptibility locus for schizophrenia and febrile seizures. Here we report the crystal structures of human IMPA2 and its complex with calcium and phosphate ions. Human IMPA2 comprises an alpha-beta protein with a five-layered sandwich of alpha-helices and beta-sheets (alpha-beta-alpha-beta-alpha). The crystal structure and analytical ultracentrifugation results indicated that IMPA2 exists as a dimer in solution. The overall structure of IMPA2 is similar to that of IMPA1, except for the loop regions. In IMPA1, the loop region (31-43) is located at the entrance of the active site cavity. In the corresponding region (42-54) of IMPA2, the residues are disordered and partially form an alpha-helix. The structural difference in the opening of the active site cavity suggests that the substrate specificity differs between IMPA1 and IMPA2. The widely opened cavity of IMPA2 implies that the physiological substrate may be a larger compound than inositol monophosphate. The structure of IMPA2 complexed with Ca2+ revealed two metals and one phosphate binding sites, which were the same sites as in IMPA1 complexed with Mn2+ and phosphate, suggesting that the mechanism of the enzymatic reaction is similar to that of IMPA1. The crystal structures of human IMPA2 are useful for understanding the effect of nonsynonymous polymorphism reported in IMPA2, and will contribute to further functional analyses of IMPA2 that potentially predisposes to the vulnerabilities of bipolar disorder, schizophrenia, and febrile seizures.
SCZ Keywordsschizophrenia,schizophrenics
8
J. Biol. Chem. 2007 Jan 282: 637-46
PMID17068342
TitleSpatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1.
AbstractLithium is used in the clinical treatment of bipolar disorder, a disease where patients suffer mood swings between mania and depression. Although the mode of action of lithium remains elusive, a putative primary target is thought to be inositol monophosphatase (IMPase) activity. Two IMPase genes have been identified in mammals, the well characterized myo-inositol monophosphatase 1 (IMPA1) and myo-inositol monophosphatase 2 (IMPA2). Several lines of genetic evidence have implicated IMPA2 in the pathogenesis of not only bipolar disorder but also schizophrenia and febrile seizures. However, little is known about the protein, although it is predicted to have lithium-inhibitable IMPase activity based on its homology to IMPA1. Here we present the first biochemical study comparing the enzyme activity of IMPA2 to that of IMPA1. We demonstrate that in vivo, IMPA2 forms homodimers but no heterodimers with IMPA1. Recombinant IMPA2 exhibits IMPase activity, although maximal activity requires higher concentrations of magnesium and a higher pH. IMPA2 shows significantly lower activity toward myo-inositol monophosphate than IMPA1. We therefore screened for additional substrates that could be more efficiently dephosphorylated by IMPA2, but failed to find any. Importantly, when using myo-inositol monophosphate as a substrate, the IMPase activity of IMPA2 was inhibited at high lithium and restricted magnesium concentrations. This kinetics distinguishes it from IMPA1. We also observed a characteristic pattern of differential expression between IMPA1 and IMPA2 in a selection of tissues including the brain, small intestine, and kidney. These data suggest that IMPA2 has a separate function in vivo from that of IMPA1.
SCZ Keywordsschizophrenia,schizophrenics


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