Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia

The alpha (1)-inhibitory glycine receptor is a ligand-gated chloride channe l composed of three ligand-binding alpha (1)-subunits and two structural be ta -subunits that are clustered on the postsynaptic membrane of inhibitory glycinergic neurons. Dominant and recessive mutations in GLRA1 subunits hav e been associated with a proportion of individuals and families with startl e disease or hyperekplexia (MIM: 149400). Following SSCP and bi-directional dideoxy fingerprinting mutational analysis of 22 unrelated individuals wit h hyperekplexia and hyperekplexia-related conditions, we report further nov el missense mutations and the first nonsense point mutations in GLRA1, the majority of which localise outside the regions previously associated with d ominant, disease-segregating mutations. Population studies reveal the uniqu e association of each mutation with disease, and reveals that a proportion of sporadic hyperekplexia is accounted for by the homozygous inheritance of recessive GLRA1 mutations or as part of a compound heterozygote.