title: Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia.
abstract: The alpha(1)-inhibitory glycine receptor is a ligand-gated chloride channel composed of three ligand-binding alpha1-subunits and two structural beta-subunits that are clustered on the postsynaptic membrane of inhibitory glycinergic neurons. Dominant and recessive mutations in GLRA1 subunits have been associated with a proportion of individuals and families with startle disease or hyperekplexia (MIM: 149400). Following SSCP and bi-directional di-deoxy fingerprinting mutational analysis of 22 unrelated individuals with hyperekplexia and hyperekplexia-related conditions, we report further novel missense mutations and the first nonsense point mutations in GLRA1, the majority of which localise outside the regions previously associated with dominant, disease-segregating mutations. Population studies reveal the unique 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.
authors.affiliation: Department of Molecular Medicine, University of Auckland Medical School, Postbag 92019, Auckland, New Zealand. m.rees@auckland.ac.nz
authors.forename: M I
authors.initials: MI
authors.lastname: Rees
authors.forename: T M
authors.initials: TM
authors.lastname: Lewis
authors.forename: B
authors.initials: B
authors.lastname: Vafa
authors.forename: C
authors.initials: C
authors.lastname: Ferrie
authors.forename: P
authors.initials: P
authors.lastname: Corry
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
authors.forename: H
authors.initials: H
authors.lastname: Jungbluth
authors.forename: J B
authors.initials: JB
authors.lastname: Stephenson
authors.forename: M
authors.initials: M
authors.lastname: Kerr
authors.forename: R G
authors.initials: RG
authors.lastname: Snell
authors.forename: P R
authors.initials: PR
authors.lastname: Schofield
authors.forename: M J
authors.initials: MJ
authors.lastname: Owen
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D018389:Codon, Nonsense; D016172:DNA Fingerprinting; D018076:DNA, Complementary / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D009122:Muscle Hypertonia / Q000235:genetics*; D020125:Mutation, Missense; D018807:Polymorphism, Single-Stranded Conformational; D018009:Receptors, Glycine / Q000235:genetics*; D012021:Reflex, Abnormal / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D018076:DNA, Complementary; C000657604:GLRA1 protein, human; D018009:Receptors, Glycine