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

Molecular Psychiatry volume 16, pages 86–96 (2011)Cite this article

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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.

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Acknowledgements

We thank all the families who participated in this research. We thank Wang Zhen Shen and Ningning Hu for their excellent technical assistance. This work was supported by National Institutes of Health Grants MH061009 and NS049261 to JSS, NS33300 and NS51590 to RLM, P50 HD055751 to EHC, P50 MH081755 to EC and a CURE research grant to JQK.

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Author notes

  1. R J Delahanty and J Q Kang: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

    R J Delahanty & J S Sutcliffe

  2. Department of Neurology, Vanderbilt University, Nashville, TN, USA

    J Q Kang & R L Macdonald

  3. Department of Psychiatry, Institute for Juvenile Research, University of Illinois at Chicago, Chicago, IL, USA

    C W Brune

  4. Department of Health Studies, The University of Chicago, Chicago, IL, USA

    E O Kistner & E H Cook Jr

  5. Department of Neurosciences, University of California San Diego, La Jolla, CA, USA

    E Courchesne

  6. Department of Medicine, The University of Chicago, Chicago, IL, USA

    N J Cox

  7. Department of Psychiatry, Vanderbilt University, Nashville, TN, USA

    J S Sutcliffe

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  1. R J Delahanty
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Delahanty, R., Kang, J., Brune, C. et al. Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. Mol Psychiatry 16, 86–96 (2011). https://doi.org/10.1038/mp.2009.118

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