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

摘要: 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 the GlyR α1 subunit gene (GLRA1) are major cause of this disorder, since remarkably few individuals with mutations β (GLRB) have been found date. Systematic DNA sequencing GLRB hyperekplexia revealed new missense GLRB, resulting M177R, L285R W310C substitutions. The recessive mutation M177R results insertion positively-charged residue into hydrophobic pocket extracellular domain, an increased EC50 decreased maximal responses α1β GlyRs. de novo side chain pore-lining 9′ position. at site known destabilize channel closed state produce spontaneously active channels. Consistent this, we identified leak conductance associated spontaneous activity cells expressing α1βL285R Peak currents were also reduced for GlyRs although glycine sensitivity was normal. predicted interfere side-chain stacking between M1, M2 M3. We that had no effect on sensitivity, but both homozygous (α1βW310C) heterozygous (α1ββW310C) stoichiometries. Since mild symptoms reported carriers, may represent example incomplete dominance disease, providing potential genetic explanation ‘minor’ form hyperekplexia.