title: 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.
authors.affiliation: Department of Biological Chemistry, University of California, Irvine 92717, USA.
authors.forename: R
authors.initials: R
authors.lastname: Shiang
authors.forename: S G
authors.initials: SG
authors.lastname: Ryan
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Zhu
authors.forename: T J
authors.initials: TJ
authors.lastname: Fielder
authors.forename: R J
authors.initials: RJ
authors.lastname: Allen
authors.forename: A
authors.initials: A
authors.lastname: Fryer
authors.forename: S
authors.initials: S
authors.lastname: Yamashita
authors.forename: P
authors.initials: P
authors.lastname: O'Connell
authors.forename: J J
authors.initials: JJ
authors.lastname: Wasmuth
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D005091:Exons; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D009127:Muscle Rigidity / Q000235:genetics*; D011110:Polymorphism, Genetic; D013216:Reflex, Startle / Q000235:genetics*