James Sutcliffe
Last active: 2/20/2014

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

Delahanty RJ, Kang JQ, Brune CW, Kistner EO, Courchesne E, Cox NJ, Cook EH, Macdonald RL, Sutcliffe JS
Mol Psychiatry. 2011 16 (1): 86-96

PMID: 19935738 · PMCID: PMC3428055 · DOI:10.1038/mp.2009.118

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.

MeSH Terms (10)

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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