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

NEUROBIOLOGY OF DISEASE

卷:52

Article

James, Victoria M.^1,2  Bode, Anna³  Chung, Seo-Kyung^4,5  Gill, Jennifer L.¹  Nielsen, Maartje^6,7  Cowan, Frances M.⁸  Vujic, Mihailo^8,9  Thomas, Rhys H.^4,5  Rees, Mark I.^4,5  Harvey, Kirsten¹  Keramidas, Angelo³  Topf, Maya²  Ginjaar, Ieke^6,7  Lynch, Joseph W.^3,10  Harvey, Robert J.¹ 

[1] UCL Sch Pharm, Dept Pharmacol, London WC1N 1AX, England

[2] Univ London Birkbeck Coll, Dept Biol Sci, Inst Struct & Mol Biol, London WC1E 7HX, England

[3] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia

[4] Swansea Univ, Coll Med, Inst Life Sci, Swansea SA2 8PP, W Glam, Wales

[5] Swansea Univ, Coll Med, Wales Epilepsy Res Network, Swansea SA2 8PP, W Glam, Wales

[6] Ctr Human, NL-2330 ZC Leiden, Netherlands

[7] Leiden Univ, Med Ctr, NL-2300 RA Leiden, Netherlands

[8] Univ London Imperial Coll Sci Technol & Med, Dept Paediat, London W12 0HS, England

[9] Sahlgrens Univ Hosp, Dept Clin Genet, SE-41345 Gothenburg, Sweden

[10] Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia

关键词: GLRA1;    GLRB;    Glycine receptor;    Hyperekplexia;    Startle disease;   

DOI  :  10.1016/j.nbd.2012.12.001

来源: Elsevier

【 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 in the GlyR alpha(1) subunit gene (GLRA1) are the major cause of this disorder, since remarkably few individuals with mutations in the GlyR beta 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 alpha(1)beta 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 alpha(1)beta(L285R) GlyRs. Peak currents were also reduced for alpha(1)beta(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 alpha(1)beta GlyRs in both homozygous (alpha(1)beta(W310C)) and heterozygous (alpha(1)beta beta(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. (C) 2012 Elsevier Inc. All rights reserved.

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