| 1 | Proc. Natl. Acad. Sci. U.S.A. 2006 May 103: 7729-34 |
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| 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 |
| 2 | 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 |
| 3 | 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 |
| 4 | 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 |
| 5 | Psychiatry Res 2011 May 187: 457-9 |
| PMID | 20538345 |
| Title | Association study between GNB1L and three major mental disorders in Chinese Han populations. |
| Abstract | We carried out an association study between GNB1L and three mental disorders (major depressive disorder, bipolar disorder, schizophrenia) in Chinese Han population. Among 1135 cases and 1135 controls, findings suggests that GNB1L is linked with bipolar disorder and schizophrenia and not with major depressive disorder. |
| SCZ Keywords | schizophrenia |
| 6 | PLoS ONE 2012 -1 7: e33473 |
| PMID | 22457764 |
| Title | Functional gene-expression analysis shows involvement of schizophrenia-relevant pathways in patients with 22q11 deletion syndrome. |
| Abstract | 22q11 Deletion Syndrome (22q11DS) is associated with dysmorphology and a high prevalence of schizophrenia-like symptoms. Several genes located on chromosome 22q11 have been linked to schizophrenia. The deletion is thought to disrupt the expression of multiple genes involved in maturation and development of neurons and neuronal circuits, and neurotransmission. We investigated whole-genome gene expression of Peripheral Blood Mononuclear Cells (PBMC's) of 8 22q11DS patients and 8 age- and gender-matched controls, to (1) investigate the expression levels of 22q11 genes and (2) to investigate whether 22q11 genes participate in functional genetic networks relevant to schizophrenia. Functional relationships between genes differentially expressed in patients (as identified by Locally Adaptive Statistical procedure (LAP) or satisfying p<0.05 and fold-change >1.5) were investigated with the Ingenuity Pathways Analysis (IPA). 14 samples (7 patients, 7 controls) passed quality controls. LAP identified 29 deregulated genes. Pathway analysis showed 262 transcripts differentially expressed between patients and controls. Functional pathways most disturbed were cell death, cell morphology, cellular assembly and organization, and cell-to-cell signaling. In addition, 10 canonical pathways were identified, among which the signal pathways for Natural Killer-cells, neurotrophin/Trk, neuregulin, axonal guidance, and Huntington's disease. Our findings support the use of 22q11DS as a research model for schizophrenia. We identified decreased expression of several genes (among which COMT, Ufd1L, PCQAP, and GNB1L) previously linked to schizophrenia as well as involvement of signaling pathways relevant to schizophrenia, of which Neurotrophin/Trk and neuregulin signaling seems to be especially notable. |
| SCZ Keywords | schizophrenia |
| 7 | 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 |
| 8 | Neurosci Bull 2015 Feb 31: 43-52 |
| PMID | 24831436 |
| Title | The schizophrenia/bipolar disorder candidate gene GNB1L is regulated in human temporal cortex by a cis-acting element located within the 3'-region. |
| Abstract | 22q11.2 deletion syndrome (DS) is a complex developmental disorder with a high incidence of psychiatric illnesses, including schizophrenia and mood disorders. Recent studies have identified Guanine Nucleotide Binding Protein (G protein) Beta Polypeptide 1-Like (GNB1L), located within the 1.5 Mbp 22q11.2 DS critical region, as a candidate liability gene for schizophrenia and bipolar disorder. In this study, we used mRNA expression measurements in Han Chinese postmortem temporal cortex and linkage disequilibrium (LD) analysis to show that GNB1L is regulated by a cis-acting genetic variant within the 3'-region of the gene. Significantly, this variant is located within an LD block that contains all of the common SNPs previously shown to associate with schizophrenia and bipolar disorder in Han Chinese and Caucasian populations. Contrary to our expectations, re-analysis of previously published case-control study data in light of our mRNA expression results implies that the GNB1L high-expression allele is the risk allele for schizophrenia and bipolar disorder in the Han Chinese population. |
| SCZ Keywords | schizophrenia |