• Victoria M James, Anna Bode, Seo-Kyung Chung, Jennifer L Gill, Maartje Nielsen, Frances M Cowan, Mihailo Vujic, Rhys H Thomas, Mark I Rees, Kirsten Harvey, Angelo Keramidas, Maya Topf, Ieke Ginjaar, Joseph W Lynch, and Robert J Harvey.
• Department of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom.
• Neurobiol. Dis. 2013 Apr 1; 52: 137-49.

AbstractStartle 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 α(1) 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 EC(50) and decreased maximal responses of α(1)β 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 α(1)β(L285R) GlyRs. Peak currents were also reduced for α(1)β(L285R) GlyRs although glycine sensitivity was normal. W310C was predicted to interfere with hydrophobic side-chain stacking between M1, M2 and M3. We found that W310C had no effect on glycine sensitivity, but reduced maximal currents in α(1)β GlyRs in both homozygous (α(1)β(W310C)) and heterozygous (α(1)ββ(W310C)) stoichiometries. Since mild startle symptoms were reported in W310C carriers, this may represent an example of incomplete dominance in startle disease, providing a potential genetic explanation for the 'minor' form of hyperekplexia.Copyright © 2012 Elsevier Inc. All rights reserved.

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