Mutational analysis of familial and sporadic hyperekplexia

Abstract

Hyperekplexia is a rare, autosomal dominant neurological disorder characterized by hypertonia, especially in infancy, and by an exaggerated startle response. This disorder is caused by mutations in the alpha 1 subunit of the inhibitory glycine receptor (GLRA1). We previously reported two GLRA1 point mutations detected in 4 unrelated hyperekplexia families; both mutations were at nucleotide 1192 and resulted in the replacement of Arg271 by a glutamine (R271Q) in one case and a leucine (R271L) in the other. Here, 5 additional hyperekplexia families are shown to have the most common G-to-A transition mutation at nucleotide 1192. Haplotype analysis using polymorphisms within and close to the GLRA1 locus suggests that this mutation has arisen at least twice (and possibly four times). In 2 additional families, a third mutation is also presented that changes a tyrosine at amino acid 279 to a cysteine (Y279C). Five patients with atypical clinical features and equivocal or absent family history of hyperekplexia and 1 patient with a classical presentation but not family history are presented in whom a mutation in the GLRA1 gene was not detected. Thus, only clinically typical hyperekplexia appears to be consistently associated with GLRA1 mutations, and these affect a specific extracellular domain of the protein.

Mutations in the GlyT2 Gene (SLC6A5) Are a Second Major Cause of Startle Disease

“…g, relative efficacy (I max /EC 50 ) of A275T/wild-type GlyT2. basis than dominant hyperekplexia, which received initial attention because of the characterization of extended families (8,9) harboring dominant GLRA1 mutations such as R271 Q/L. In common with previous studies (17,18), genotype-phenotype analysis revealed that GlyT2 mutations in humans are not as severe as those observed in mice, dogs, and cattle, where mutations in SLC6A5 cause extreme muscle rigidity, tremor, difficulty in breathing, and early mortality (19,20,44).…”

A Short Guide to Electrophysiology and Ion Channels

“…Glycine receptors also have a role in processing visual and auditory signals (69). There are a number of known malfunctions of CLRs including mutations of muscle nAChRs, which lead to congenital myasthenic syndromes, mutations of GABAA and nAChRs cause epilepsy (70), and glycine receptor mutations lead to hyperekplexia (71,72).…”

Glycine Receptor: Molecular Organization and Pathology

“…R271Q та R271L, розташова-ні на зовнішньоклітинному кінці ТМ2-домену, є найбільш частими та найбільш вивченими гіперплексичними мутаціями. Вони успадковуються аутосомно домінантно [65,[77][78][79]. Ці мутації не змінюють кількість гліцинових рецепторів на поверхні клітини, однак сильно впливають на їх чутливість до гліцину та провідність каналів [81,82,90].…”