Glycine Transporter Mutations in Hyperekplexia
Hyperekplexia is a paroxysmal disorder that is typified by excessive startle response in reaction to sudden sounds or tactile sensation. The hypertonic state results in exaggerated fall-down episodes that are often confused with an epileptic disorder or arrhythmia syncope. The disorder has a genetic aetiology associated with glycinergic receptor subunits mutations in GlyR α1 (GLRA1) and β-subunit (GLRB) loci. Having excluded mutations in GLRA1 and GLRB from a large proportion of our sporadic sample of hyperekplexia patients, we have conducted an extensive search for more predisposition genes in the wider glycinergic and GABAergic proteomes. As a result, a third major gene of effect was identified in several sporadic hyperekplexia patients, and two affected-member pedigrees. The mutations were found is the glycine transporter gene and inherited in recessive form with compound heterozygosity for missense and nonsense present in affected individuals. Carrier parents were asymptomatic and new gene is not susceptible to haploinsufficiency. The pathogenicity of these mutations were confirmed by population screening in normal controls, neurotransmitter uptake assays of mutant alleles, electrophysiology, and neuronal primary culture imaging. This confirms that hyperekplexia is truly a heterogeneous genetic disorder with mostly-dominant GLRA1 cases now sharing major gene status with a second locus that is predominantly inherited in recessive manner. This, in combination with rare GLRA1 and GLRB compound heterozygosity, goes some way to explain the occurrence of sporadic hyperekplexia