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‣ Novel missense mutations in the glycine receptor β subunit gene (GLRB) in startle disease

James, Victoria M.; Bode, Anna; Chung, Seo-Kyung; Gill, Jennifer L.; Nielsen, Maartje; Cowan, Frances M.; Vujic, Mihailo; Thomas, Rhys H.; Rees, Mark I.; Harvey, Kirsten; Keramidas, Angelo; Topf, Maya; Ginjaar, Ieke; Lynch, Joseph W.; Harvey, Robert J.
Fonte: Academic Press Publicador: Academic Press
Tipo: Artigo de Revista Científica
Publicado em /04/2013 Português
Relevância na Pesquisa
481.26105%
Startle disease is a rare, potentially fatal neuromotor disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden unexpected auditory, visual or tactile stimuli. Mutations in the GlyR α1 subunit gene (GLRA1) are the major cause of this disorder, since remarkably few individuals with mutations in the GlyR β subunit gene (GLRB) have been found to date. Systematic DNA sequencing of GLRB in individuals with hyperekplexia revealed new missense mutations in GLRB, resulting in M177R, L285R and W310C substitutions. The recessive mutation M177R results in the insertion of a positively-charged residue into a hydrophobic pocket in the extracellular domain, resulting in an increased EC50 and decreased maximal responses of α1β GlyRs. The de novo mutation L285R results in the insertion of a positively-charged side chain into the pore-lining 9′ position. Mutations at this site are known to destabilize the channel closed state and produce spontaneously active channels. Consistent with this, we identified a leak conductance associated with spontaneous GlyR activity in cells expressing α1βL285R GlyRs. Peak currents were also reduced for α1βL285R GlyRs although glycine sensitivity was normal. W310C was predicted to interfere with hydrophobic side-chain stacking between M1...