Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism.
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.
Delahanty
R J
RJ
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232-8548, USA.
Kang
J Q
JQ
Brune
C W
CW
Kistner
E O
EO
Courchesne
E
E
Cox
N J
NJ
Cook
E H
EH
Macdonald
R L
RL
Sutcliffe
J S
JS
D001321:Autistic Disorder / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15; D005260:Female; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000235:genetics*
C546273:GABRB3 protein, human; D011963:Receptors, GABA-A