Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232-8548, USA.
Molecular Psychiatry (Impact Factor: 14.5). 11/2009; 16(1):86-96. DOI: 10.1038/mp.2009.118
Source: PubMed


Maternal 15q11-q13 duplication is the most common copy number variant in autism, accounting for ∼1-3% of cases. The 15q11-q13 region is subject to epigenetic regulation, and genomic copy number losses and gains cause genomic disorders in a parent-of-origin-specific manner. One 15q11-q13 locus encodes the GABA(A) receptor β3 subunit gene (GABRB3), which has been implicated by several studies in both autism and absence epilepsy, and the co-morbidity of epilepsy in autism is well established. We report that maternal transmission of a GABRB3 signal peptide variant (P11S), previously implicated in childhood absence epilepsy, is associated with autism. An analysis of wild-type and mutant β3 subunit-containing α1β3γ2 or α3β3γ2 GABA(A) receptors shows reduced whole-cell current and decreased β3 subunit protein on the cell surface due to impaired intracellular β3 subunit processing. We thus provide the first evidence of an association between a specific GABA(A) receptor defect and autism, direct evidence that this defect causes synaptic dysfunction that is autism relevant and the first maternal risk effect in the 15q11-q13 autism duplication region that is linked to a coding variant.


Available from: James S Sutcliffe, Jun 20, 2014
  • Source
    • "Missense mutations of GABRB3 have been reported to be associated with childhood absence epilepsy (P11S, S15F, G32R) [64,65], insomnia (R192H) [66], and autism (P11S) [67]. In this study, we did not detect these missense mutations in our samples. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BackgroundGABRB3 is a position candidate gene at chromosome 15q12 that has been implicated in the neurobiology of autism spectrum disorders (ASD). The aim of this study was to examine the genetic association of GABRB3 with ASD.MethodsThe sample consisted of 356 patients with clinical diagnosis of ASD according to the DSM-IV diagnostic criteria and confirmed by the Autism Diagnostic Interview-Revised and 386 unrelated controls. We searched for mutations at all the exonic regions and 1.6 Kb of the 5′ region of GABRB3 in the genomic DNA of all the participants using the Sanger sequencing. We implemented a case-control association analysis of variants detected in this sample, and conducted a reporter gene assay to assess the functional impact of variants at the 5′ regulatory region.ResultsWe detected six known common SNPs; however, they were not associated with ASD. Besides, a total of 22 rare variants (12 at 5′ regulatory, 4 at intronic, and 6 at exonic regions) were detected in 18 patients and 6 controls. The frequency of rare variants was significantly higher in the patient group than in the control group (18/356 versus 6/386, odds ratio = 3.37, P = 0.007). All the 12 rare variants at the 5′ regulatory region were only detected in 7 patients, but not in any of the controls (7/356 versus 0/386, Fisher’s exact test, P = 0.006). Two patients carried multiple rare variants. Family studies showed that most of these rare variants were transmitted from their parents. Reporter gene assays revealed that four rare variants at the 5′ regulatory region and 1 at exon 1a untranslated region had elevated reporter gene activities compared to two wild type alleles.ConclusionsOur data suggest rare variants of GABRB3 might be associated with ASD, and increased GABRB3 expression may contribute to the pathogenesis of ASD in some patients.Trial registrationClinical trial registration Identifier: NCT00494754
    Molecular Autism 06/2014; 5(1):36. DOI:10.1186/2040-2392-5-36 · 5.41 Impact Factor
  • Source
    • "This was replicated in 80 autism families [13]. Copy number variations and other chromosomal abnormalities at the GABRB3 locus have also been reported in individuals with ASC [14,18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autism spectrum conditions (ASC) are associated with deficits in social interaction and communication, alongside repetitive, restricted, and stereotyped behavior. ASC is highly heritable. The gamma-aminobutyric acid (GABA)-ergic system has been associated consistently with atypicalities in autism, in both genetic association and expression studies. A key component of the GABA-ergic system is encoded by the GABRB3 gene, which has been previously implicated both in ASC and in individual differences in empathy. In this study, 45 genotyped single nucleotide polymorphisms (SNPs) within GABRB3 were tested for association with Asperger syndrome (AS), and related quantitative traits measured through the following tests: the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ), the Systemizing Quotient-Revised (SQ-R), the Embedded Figures Test (EFT), the Reading the Mind in the Eyes Test (RMET), and the Mental Rotation Test (MRT). Two-loci, three-loci, four-loci haplotype analyses, and one seven-loci haplotype analysis were also performed in the AS case--control sample. Three SNPs (rs7180158, rs7165604, rs12593579) were significantly associated with AS, and two SNPs (rs9806546, rs11636966) were significantly associated with EQ. Two SNP-SNP pairs, rs12438141-rs1035751 and rs12438141-rs7179514, showed significant association with variation in the EFT scores. One SNP-SNP pair, rs7174437-rs1863455, was significantly associated with variation in the MRT scores. Additionally, a few haplotypes, including a 19 kb genomic region that formed a linkage disequilibrium (LD) block in our sample and contained several nominally significant SNPs, were found to be significantly associated with AS. The current study confirms the role of GABRB3 as an important candidate gene in both ASC and normative variation in related endophenotypes.
    Molecular Autism 12/2013; 4(1):48. DOI:10.1186/2040-2392-4-48 · 5.41 Impact Factor
  • Source
    • "Paternal transmission was associated with a trend for a younger age at onset in probands compared to that observed in the case of maternal transmission in periodic catatonia.[19] Rare copy number variants have been considered in neurodevelopmental disorders.[20] It has been documented recently that the presence of micro-duplications at chromosome 15q11.2-q13.1 that overlaps with the Prader-Willi/Angelman syndrome critical region may bear are risk factor for schizophrenia and other psychoses, emphasizing a possible POE.[21] "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study aims at examining "parent-of-origin effect" (POE) in dermatoglyphic patterns among patients with schizophrenia and non-affective psychoses. Dermatoglyphic comparison was carried out for schizophrenia patients (n=200) and healthy controls (HC) (n=100). In addition, the effect of family history and POE was examined in the dermatoglyphic pattern. Schizophrenia patients compared to HC had significantly lower left total finger ridge count (LTFRC) (t=3.63, P<0.001), right total finger ridge count (RTFRC) (t=4.86, P<0.001), and absolute finger ridge count (ATFRC) (t=4.80, P<0.001) compared to HC. It was also noted that patient group had significantly higher average number of arches (t=2.20, P=0.03). The comparison between the same sex POE group and the opposite sex POE group revealed that significant differences exist in LTFRC (t=2.91, P<0.01) and ATFRC (t=2.30, P=0.02). The same sex group also had lesser number of whorls compared to opposite sex group (t=2.04, P=0.04). The same sex parental inheritance group seem to be more developmentally compromised than the opposite sex parental inheritance group indicating a significant POE. Complex epigenetic mechanisms along with hormonal modulation could explain the sex specific disease phenotype expression, which is a plausible explanation as in the present study.
    Indian Journal of Psychological Medicine 07/2013; 35(3):260-7. DOI:10.4103/0253-7176.119481
Show more