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

Molecular psychiatry | Jan 23, 2011

http://www.ncbi.nlm.nih.gov/pubmed/19935738

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.

Pubmed ID: 19935738 RIS Download

Mesh terms: Autistic Disorder | Chromosomes, Human, Pair 15 | Female | Genome-Wide Association Study | Germ-Line Mutation | Humans | Male | Pedigree | Polymorphism, Single Nucleotide | Receptors, GABA-A

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Associated grants

  • Agency: Autism Speaks, Id: AS1583
  • Agency: NIMH NIH HHS, Id: MH061009
  • Agency: NINDS NIH HHS, Id: NS049261
  • Agency: NINDS NIH HHS, Id: NS33300
  • Agency: NINDS NIH HHS, Id: NS51590
  • Agency: NICHD NIH HHS, Id: P50 HD055751
  • Agency: NICHD NIH HHS, Id: P50 HD055751
  • Agency: NICHD NIH HHS, Id: P50 HD055751-03
  • Agency: NIMH NIH HHS, Id: P50 MH081755
  • Agency: NIMH NIH HHS, Id: P50 MH081755-01
  • Agency: NINDS NIH HHS, Id: R01 NS051590

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