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

Original Article - click here for text.

Molecular Psychiatry advance online publication 24 November 2009; doi: 10.1038/mp.2009.118

R J Delahanty^1,8, J Q Kang^2,8, C W Brune³, E O Kistner⁴, E Courchesne⁵, N J Cox⁶, E H Cook Jr⁴, R L Macdonald² and J S Sutcliffe^1,7

1. ¹Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
2. ²Department of Neurology, Vanderbilt University, Nashville, TN, USA
3. ³Department of Psychiatry, Institute for Juvenile Research, University of Illinois at Chicago, Chicago, IL, USA
4. ⁴Department of Health Studies, The University of Chicago, Chicago, IL, USA
5. ⁵Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
6. ⁶Department of Medicine, The University of Chicago, Chicago, IL, USA
7. ⁷Department of Psychiatry, Vanderbilt University, Nashville, TN, USA

Correspondence: Dr JS Sutcliffe, Center for Molecular Neuroscience, Departments of Molecular Physiology and Biophysics and Psychiatry, Vanderbilt University, Nashville, TN 37232-8548, USA. E-mail:jim.sutcliffe@vanderbilt.edu

⁸These two authors contributed equally to this work.

Received 7 July 2009; Revised 10 September 2009; Accepted 22 September 2009; Published online 24 November 2009.

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 3 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 3 subunit-containing 132 or 332 GABA_A receptors shows reduced whole-cell current and decreased 3 subunit protein on the cell surface due to impaired intracellular 3 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.