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

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Bibliographic Details
Title:	Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism.
Authors:	Delahanty, R. J., Kang, J. Q., Brune, C. W., Kistner, E. O., Courchesne, E., Cox, N. J., Cook,Jr., E. H., Macdonald, R. L., Sutcliffe, J. S.
Source:	Molecular Psychiatry. Jan2011, Vol. 16 Issue 1, p86-96. 11p. 1 Diagram, 1 Chart, 3 Graphs.
Subjects:	Brain diseases, Autism, Epilepsy, Genetics, Genetic mutation
Abstract:	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 GABAA 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 GABAA 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 GABAA 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. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

Description
Abstract:	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 GABAA 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 GABAA 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 GABAA 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. [ABSTRACT FROM AUTHOR]
ISSN:	13594184
DOI:	10.1038/mp.2009.118