| 1 | Proc. Natl. Acad. Sci. U.S.A. 2003 Nov 100: 14433-8 |
|---|---|
| PMID | 14614146 |
| Title | A comprehensive analysis of 22q11 gene expression in the developing and adult brain. |
| Abstract | Deletions at 22q11.2 are linked to DiGeorge or velocardiofacial syndrome (VCFS), whose hallmarks include heart, limb, and craniofacial anomalies, as well as learning disabilities and increased incidence of schizophrenia. To assess the potential contribution of 22q11 genes to cognitive and psychiatric phenotypes, we determined the CNS expression of 32 mouse orthologs of 22q11 genes, primarily in the 1.5-Mb minimal critical region consistently deleted in VCFS. None are uniquely expressed in the developing or adult mouse brain. Instead, 27 are localized in the embryonic forebrain as well as aortic arches, branchial arches, and limb buds. Each continues to be expressed at apparently constant levels in the fetal, postnatal, and adult brain, except for TBX1, ProDH2, and T10, which increase in adolescence and decline in maturity. At least six 22q11 proteins are seen primarily in subsets of neurons, including some in forebrain regions thought to be altered in schizophrenia. Thus, 22q11 deletion may disrupt expression of multiple genes during development and maturation of neurons and circuits compromised by cognitive and psychiatric disorders associated with VCFS. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 2 | Curr Psychiatry Rep 2004 Jun 6: 176-82 |
| PMID | 15142470 |
| Title | Genetic abnormalities of chromosome 22 and the development of psychosis. |
| Abstract | A microdeletion at chromosome 22q11 is the most frequently known interstitial deletion found in humans, occurring in approximately one of every 4000 live births. Its occurrence is associated with a characteristic facial dysmorphology, a range of congenital abnormalities, and psychiatric problems, especially schizophrenia. The prevalence of psychosis in those with 22q11 deletion syndrome is high (30%), suggesting that haploinsufficiency of a gene or genes in this region may confer a substantially increased risk. In addition, several studies provide evidence for linkage to schizophrenia on 22q, suggesting that a gene in this region could confer susceptibility to schizophrenia in nondeleted cases. Recent studies have provided compelling evidence that haploinsufficiency of TBX1 is likely to be responsible for many of the physical features associated with the deletion. However, although a number of genes have been implicated as possible schizophrenia susceptibility loci, further confirmatory studies are required. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 3 | 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, schizophrenics |
| 4 | Proc. Natl. Acad. Sci. U.S.A. 2005 Dec 102: 19132-7 |
| PMID | 16365290 |
| Title | A 200-kb region of human chromosome 22q11.2 confers antipsychotic-responsive behavioral abnormalities in mice. |
| Abstract | Human chromosome 22q11.2 has been implicated in various behavioral abnormalities, including schizophrenia and other neuropsychiatric/behavioral disorders. However, the specific genes within 22q11.2 that contribute to these disorders are still poorly understood. Here, we show that an approximately 200-kb segment of human 22q11.2 causes specific behavioral abnormalities in mice. Mice that overexpress an approximately 200-kb region of human 22q11.2, containing CDCrel, GP1Bbeta, TBX1, and WDR14, exhibited spontaneous sensitization of hyperactivity and a lack of habituation. These effects were ameliorated by antipsychotic drugs. The transgenic mice were also impaired in nesting behavior. Although TBX1 has been shown to be responsible for many physical defects associated with 22q11.2 haploinsufficiency, TBX1 heterozygous mice did not display these behavioral abnormalities. Our results show that the approximately 200-kb region of 22q11.2 contains a gene(s) responsible for behavioral abnormalities and suggest that distinct genetic components within 22q11.2 mediate physical and behavioral abnormalities. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 5 | Neurogenetics 2006 Nov 7: 247-57 |
| PMID | 16900388 |
| Title | Behavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome. |
| Abstract | Velocardiofacial/DiGeorge syndrome (VCFS/DGS) is a developmental disorder caused by a 1.5 to 3-Mb hemizygous 22q11.2 deletion. VCFS/DGS patients display malformations in multiple systems, as well as an increased frequency of neuropsychiatric defects including schizophrenia. Haploinsufficiency of TBX1 appears to be responsible for these physical malformations in humans and mice, but the genes responsible for the neuropsychiatric defects are unknown. In this study, two mouse models of VCFS/DGS, a deletion mouse model (Lgdel/+) and a single gene model (TBX1 +/-), as well as a third mouse mutant (Gscl -/-) for a gene within the Lgdel deletion, were tested in a large behavioral battery designed to assess gross physical features, sensorimotor reflexes, motor activity nociception, acoustic startle, sensorimotor gating, and learning and memory. Lgdel/+ mice contain a 1.5-Mb hemizygous deletion of 27 genes in the orthologous region on MMU 16 and present with impairment in sensorimotor gating, grip strength, and nociception. TBX1 +/- mice were impaired in grip strength similar to Lgdel/+ mice and movement initiation. Gscl -/- mice were not impaired in any of the administered tests, suggesting that redundant function of other Gsc family members may compensate for the loss of Gscl. Thus, although deletion of the genes in the Lgdel region in mice may recapitulate some of the behavioral phenotypes seen in humans with VCFS/DGS, these phenotypes are not found in mice with complete loss of Gscl or in mice with heterozygous loss of TBX1, suggesting that the neuropsychiatric and physical malformations of VCFS/DGS may act by different genetic mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 6 | Proc. Natl. Acad. Sci. U.S.A. 2006 May 103: 7729-34 |
| PMID | 16684884 |
| Title | Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome. |
| Abstract | About 35% of patients with 22q11 deletion syndrome (22q11DS), which includes DiGeorge and velocardiofacial syndromes, develops psychiatric disorders, mainly schizophrenia and bipolar disorder. We previously reported that mice carrying a multigene deletion (Df1) that models 22q11DS have reduced prepulse inhibition (PPI), a behavioral abnormality and schizophrenia endophenotype. Impaired PPI is associated with several psychiatric disorders, including those that occur in 22q11DS, and recently, reduced PPI was reported in children with 22q11DS. Here, we have mapped PPI deficits in a panel of mouse mutants that carry deletions that partially overlap with Df1 and have defined a PPI critical region encompassing four genes. We then used single-gene mutants to identify the causative genes. We show that PPI deficits in Df1/+ mice are caused by haploinsufficiency of two genes, TBX1 and Gnb1l. Mutation of either gene is sufficient to cause reduced PPI. TBX1 is a transcription factor, the mutation of which is sufficient to cause most of the physical features of 22q11DS, but the gene had not been previously associated with the behavioral/psychiatric phenotype. A likely role for TBX1 haploinsufficiency in psychiatric disease is further suggested by the identification of a family in which the phenotypic features of 22q11DS, including psychiatric disorders, segregate with an inactivating mutation of TBX1. One family member has Asperger syndrome, an autistic spectrum disorder that is associated with reduced PPI. Thus, TBX1 and Gnb1l are strong candidates for psychiatric disease in 22q11DS patients and candidate susceptibility genes for psychiatric disease in the wider population. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 7 | J. Hum. Genet. 2006 -1 51: 1037-45 |
| PMID | 16969581 |
| Title | Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia. |
| Abstract | schizophrenia is a severe, debilitating mental disorder characterized by profound disturbances of cognition, emotion and social functioning. The lifetime morbid risk is surprisingly uniform at slightly less than 1% across different populations and different cultures. The evidence of genetic risk factors is our strongest clue to the cause of schizophrenia. Linkage and association analyses have identified genes associated with the development of schizophrenia. However, most of the alleles or haplotypes identified thus far have only a weak association or are reported to be population specific. A deletion of 22q11.2 that causes the most common microdeletion syndrome (22q11DS) with an estimated prevalence of 1:2,500-1:4,000 live births may represent one of the greatest known genetic risk factors for schizophrenia. schizophrenia is a late manifestation in approximately 30% of patients with 22q11.2 deletion, comparable to the risk to offspring of two parents with schizophrenia. Clinical and neuroimaging assessments indicate that 22q11DS-schizophrenia is a neurodevelopmental model of schizophrenia. Recent studies have provided evidence that haploinsufficiency of TBX1 is likely to be responsible for many of the physical features associated with the deletion. Most of the genes in the 22q11 deletion region are conserved together on mouse chromosome 16, enabling the generation of mouse models. Similarities in the cardiovascular and other phenotypes between 22q11DS patients and mouse models can provide important insights into roles of genes in neurobehavioral phenotypes. Because more than one gene in the 22q11DS region is likely to contribute to the marked risk for schizophrenia, further extensive studies are necessary. Analyses of 22q11DS will help clarify the molecular pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 8 | Biol. Psychiatry 2006 Jun 59: 1172-9 |
| PMID | 16616724 |
| Title | Mouse models of 22q11 deletion syndrome. |
| Abstract | 22q11 deletion syndrome (22q11DS) is caused by an interstitial chromosomal microdeletion that encompasses about 40 genes. It is the most common of the microdeletion syndromes. The clinical phenotype, which is complex and variable, includes specific congenital defects of the cardiovascular system, craniofacies, and immune system. In early childhood, patients manifest cognitive impairment, behavioral disorders, and delays in motor development and language acquisition. Adult patients have a high risk for developing serious psychiatric disorders, especially schizophrenia, schizoaffective disorder, and bipolar disorder. The great majority of patients have an identical or near identical chromosomal deletion, and genotype-phenotype correlations have not been established. Indeed, little progress was made toward resolving the complex clinical phenotype until the deletion was successfully modeled in the mouse. In recent years, through a variety of mouse mutants that carry multigene and single gene mutations, we have learned that mutation in a single gene, TBX1, is responsible for most of the congenital defects seen in the mouse models and in patients. We now face a greater challenge as we attempt to use the mouse to address the pathogenesis of the behavioral and psychiatric disorders associated with 22q11DS. Significant progress has already been made, and recent studies in the mouse suggest that several genes from the deleted region affect behavior and might contribute to disease burden in patients. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 9 | 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, schizophrenics |
| 10 | Neurosci. Lett. 2007 Oct 425: 146-50 |
| PMID | 17850965 |
| Title | An association study between the genetic polymorphisms within TBX1 and schizophrenia in the Chinese population. |
| Abstract | The strong association between common psychiatric disorders and the 22q11.2 microdeletion suggests that haploinsufficiency of one or more genes in the region confers susceptibility to these disorders. Recent mouse studies have shown that the T-box 1 (TBX1) gene in the 22q11.2 region can cause prepulse inhibition (PPI) impairment in the heterozygous state. A study has also shown that phenotypic features of 22q11 deletion syndrome (22q11DS) were segregated with an inactivating mutation of TBX1 in one family, suggesting that the TBX1 gene plays a role in the pathogenesis of some psychiatric disorders. We performed an association study between three single nucleotide polymorphisms (SNPs) in the TBX1 gene and schizophrenia. However, we found no significant difference in the genotype or allele distributions between the 328 schizophrenics and 288 controls for any of the polymorphisms, nor was there any haplotype association. Our data suggest that the genetic polymorphisms within TBX1 do not confer an increased susceptibility to schizophrenia in the Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 11 | Neurosci. Lett. 2007 Oct 425: 146-50 |
| PMID | 17850965 |
| Title | An association study between the genetic polymorphisms within TBX1 and schizophrenia in the Chinese population. |
| Abstract | The strong association between common psychiatric disorders and the 22q11.2 microdeletion suggests that haploinsufficiency of one or more genes in the region confers susceptibility to these disorders. Recent mouse studies have shown that the T-box 1 (TBX1) gene in the 22q11.2 region can cause prepulse inhibition (PPI) impairment in the heterozygous state. A study has also shown that phenotypic features of 22q11 deletion syndrome (22q11DS) were segregated with an inactivating mutation of TBX1 in one family, suggesting that the TBX1 gene plays a role in the pathogenesis of some psychiatric disorders. We performed an association study between three single nucleotide polymorphisms (SNPs) in the TBX1 gene and schizophrenia. However, we found no significant difference in the genotype or allele distributions between the 328 schizophrenics and 288 controls for any of the polymorphisms, nor was there any haplotype association. Our data suggest that the genetic polymorphisms within TBX1 do not confer an increased susceptibility to schizophrenia in the Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 12 | 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, schizophrenics |
| 13 | Hum. Mol. Genet. 2008 Feb 17: 555-66 |
| PMID | 18003636 |
| Title | Strong evidence that GNB1L is associated with schizophrenia. |
| Abstract | Evidence that a gene or genes on chromosome 22 is involved in susceptibility to schizophrenia comes from two sources: the increased incidence of schizophrenia in individuals with 22q11 deletion syndrome (22q11DS) and genetic linkage studies. In mice, hemizygous deletion of either TBX1 or Gnb1l can cause deficits in pre-pulse inhibition, a sensory motor gating defect which is associated with schizophrenia. We tested the hypothesis that variation at this locus confers risk of schizophrenia and related disorders in a series of case-control association studies. First, we found evidence for a male-specific genotypic association (P = 0.00017) TBX1/GNB1L in 662 schizophrenia cases and 1416 controls from the UK. Moreover, we replicated this finding in two independent case-control samples (additional 746 cases and 1330 controls) (meta analysis P = 1.8 x 10(-5)) and also observed significant evidence for genotypic association in an independent sample of 480 schizophrenia parent-proband trios from Bulgaria with markers at this locus, which was again strongest in the male probands (P = 0.004). Genotyping the most significant SNPs in a sample of 83 subjects with 22q11DS with and without psychosis again revealed a significant allelic association with psychosis in males with 22q11DS (P = 0.01). Finally, using allele specific expression analysis, we have shown that the markers associated with psychosis are also correlated with alterations in GNB1L expression, raising the hypothesis that the risk to develop psychosis at this locus could be mediated in a dose sensitive manner via gene expression. However, other explanations are possible, and further analyses will be required to clarify the correct functional mechanism. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 14 | 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, schizophrenics |
| 15 | Schizophr Bull 2010 Jul 36: 756-65 |
| PMID | 19011233 |
| Title | Supportive evidence for reduced expression of GNB1L in schizophrenia. |
| Abstract | Chromosome 22q11 deletion syndrome (22q11DS) increases the risk of development of schizophrenia more than 10 times compared with that of the general population, indicating that haploinsufficiency of a subset of the more than 20 genes contained in the 22q11DS region could increase the risk of schizophrenia. In the present study, we screened for genes located in the 22q11DS region that are expressed at lower levels in postmortem prefrontal cortex of patients with schizophrenia than in those of controls. Gene expression was screened by Illumina Human-6 Expression BeadChip arrays and confirmed by real-time reverse transcription-polymerase chain reaction assays and Western blot analysis. Expression of GNB1L was lower in patients with schizophrenia than in control subjects in both Australian (10 schizophrenia cases and 10 controls) and Japanese (43 schizophrenia cases and 11 controls) brain samples. TBX1 could not be evaluated due to its low expression levels. Expression levels of the other genes were not significantly lower in patients with schizophrenia than in control subjects. Association analysis of tag single-nucleotide polymorphisms in the GNB1L gene region did not confirm excess homozygosity in 1918 Japanese schizophrenia cases and 1909 Japanese controls. Haloperidol treatment for 50 weeks increased Gnb1l gene expression in prefrontal cortex of mice. Taken together with the impaired prepulse inhibition observed in heterozygous Gnb1l knockout mice reported by the previous study, the present findings support assertions that GNB1L is one of the genes in the 22q11DS region responsible for increasing the risk of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 16 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jan 159B: 61-71 |
| PMID | 22095694 |
| Title | Evidence for involvement of GNB1L in autism. |
| Abstract | Structural variations in the chromosome 22q11.2 region mediated by nonallelic homologous recombination result in 22q11.2 deletion (del22q11.2) and 22q11.2 duplication (dup22q11.2) syndromes. The majority of del22q11.2 cases have facial and cardiac malformations, immunologic impairments, specific cognitive profile and increased risk for schizophrenia and autism spectrum disorders (ASDs). The phenotype of dup22q11.2 is frequently without physical features but includes the spectrum of neurocognitive abnormalities. Although there is substantial evidence that haploinsufficiency for TBX1 plays a role in the physical features of del22q11.2, it is not known which gene(s) in the critical 1.5?Mb region are responsible for the observed spectrum of behavioral phenotypes. We identified an individual with a balanced translocation 46,XY,t(1;22)(p36.1;q11.2) and a behavioral phenotype characterized by cognitive impairment, autism, and schizophrenia in the absence of congenital malformations. Using somatic cell hybrids and comparative genomic hybridization (CGH) we mapped the chromosome-22 breakpoint within intron 7 of the GNB1L gene. Copy number evaluations and direct DNA sequencing of GNB1L in 271 schizophrenia and 513 autism cases revealed dup22q11.2 in two families with autism and private GNB1L missense variants in conserved residues in three families (P?=?0.036). The identified missense variants affect residues in the WD40 repeat domains and are predicted to have deleterious effects on the protein. Prior studies provided evidence that GNB1L may have a role in schizophrenia. Our findings support involvement of GNB1L in ASDs as well. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 17 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Dec 168: 649-59 |
| PMID | 26198764 |
| Title | Genome-wide association study of schizophrenia in Ashkenazi Jews. |
| Abstract | schizophrenia is a common, clinically heterogeneous disorder associated with lifelong morbidity and early mortality. Several genetic variants associated with schizophrenia have been identified, but the majority of the heritability remains unknown. In this study, we report on a case-control sample of Ashkenazi Jews (AJ), a founder population that may provide additional insights into genetic etiology of schizophrenia. We performed a genome-wide association analysis (GWAS) of 592 cases and 505 controls of AJ ancestry ascertained in the US. Subsequently, we performed a meta-analysis with an Israeli AJ sample of 913 cases and 1640 controls, followed by a meta-analysis and polygenic risk scoring using summary results from Psychiatric GWAS Consortium 2 schizophrenia study. The U.S. AJ sample showed strong evidence of polygenic inheritance (pseudo-R(2) ?9.7%) and a SNP-heritability estimate of 0.39 (P?=?0.00046). We found no genome-wide significant associations in the U.S. sample or in the combined US/Israeli AJ meta-analysis of 1505 cases and 2145 controls. The strongest AJ specific associations (P-values in 10(-6) -10(-7) range) were in the 22q 11.2 deletion region and included the genes TBX1, GLN1, and COMT. Supportive evidence (meta P? |
| SCZ Keywords | schizophrenia, schizophrenics |
| 18 | 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, schizophrenics |
| 19 | 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, schizophrenics |
| 20 | Cereb. Cortex 2016 Mar -1: -1 |
| PMID | 27005988 |
| Title | Cortical Development Requires Mesodermal Expression of Tbx1, a Gene Haploinsufficient in 22q11.2 Deletion Syndrome. |
| Abstract | In mammals, proper temporal control of neurogenesis and neural migration during embryonic development ensures correct formation of the cerebral cortex. Changes in the distribution of cortical projection neurons and interneurons are associated with behavioral disorders and psychiatric diseases, including schizophrenia and autism, suggesting that disrupted cortical connectivity contributes to the brain pathology.TBX1is the major candidate gene for 22q11.2 deletion syndrome (22q11.2DS), a chromosomal deletion disorder characterized by a greatly increased risk for schizophrenia. We have previously shown thatTBX1heterozygous mice have reduced prepulse inhibition, a behavioral abnormality that is associated with 22q11.2DS and nonsyndromic schizophrenia. Here, we show that loss ofTBX1disrupts corticogenesis in mice by promoting premature neuronal differentiation in the medio-lateral embryonic cortex, which gives rise to the somatosensory cortex (S1). In addition, we found altered polarity in both radially migrating excitatory neurons and tangentially migrating inhibitory interneurons. Together, these abnormalities lead to altered lamination in the S1 at the terminal stages of corticogenesis inTBX1null mice and similar anomalies inTBX1heterozygous adult mice. Finally, we show that mesoderm-specific inactivation ofTBX1is sufficient to recapitulate the brain phenotype indicating thatTBX1exerts a cell nonautonomous role in cortical development from the mesoderm. |
| SCZ Keywords | schizophrenia, schizophrenics |