GABA-A receptors – ion channel receptors composed of five protein subunits – maintain inhibitory tone in the brain, and mutations in single subunit genes (GABRs) are associated with inherited forms of epilepsy. Many variations have been identified in GABRs, but molecular characterization of their contribution as susceptibility alleles for sporadic genetic epilepsies is missing.
Ciria Hernandez, M.D., Ph.D., Robert Macdonald, M.D., Ph.D., and colleagues investigated the effects of 32 GABR variants on receptor function and biogenesis.
They reported Sept. 13 in the journal PLOS ONE that variants scored as deleterious reduced GABA-A receptor function. The variants were associated with a reduction in channel “gating” and were predicted to cause structural rearrangements of the receptor.
The findings confirm the deleterious effects of GABR variants and suggest that functional defects in one or more GABRs might confer additive risk for genetic epilepsies. The researchers note that molecular diagnosis of sporadic genetic epilepsies will improve treatment by using a personalized approach.
This research was supported by a grant from the National Institutes of Health (NS033300).
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