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

• Published in: Human genetics 2001-09, Vol.109 (3), p.267-270
• Main Authors: Rees, M I, Lewis, T M, Vafa, B, Ferrie, C, Corry, P, Muntoni, F, Jungbluth, H, Stephenson, J B, Kerr, M, Snell, R G, Schofield, P R, Owen, M J
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Base Sequence; Codon, Nonsense; DNA Fingerprinting; DNA, Complementary - genetics; Heterozygote; Humans; Muscle Hypertonia - genetics; Mutation, Missense; Polymorphism, Single-Stranded Conformational; Receptors, Glycine - genetics; Reflex, Abnormal - genetics; Reflex, Startle - genetics
• ISSN: 0340-6717
• DOI: 10.1007/s004390100569

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.