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. and Harvey, Robert J. (2013) Novel missense mutations in the glycine receptor β subunit gene (GLRB) in startle disease. Neurobiology of Disease, 52 137-149. doi:10.1016/j.nbd.2012.12.001

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Author 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.
Title Novel missense mutations in the glycine receptor β subunit gene (GLRB) in startle disease
Journal name Neurobiology of Disease   Check publisher's open access policy
ISSN 0969-9961
Publication date 2013-04
Year available 2012
Sub-type Article (original research)
DOI 10.1016/j.nbd.2012.12.001
Open Access Status File (Author Post-print)
Volume 52
Start page 137
End page 149
Total pages 13
Place of publication Maryland Heights, MO, United States
Publisher Academic Press
Collection year 2013
Language eng
Formatted abstract
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, M2 and M3. We found that W310C had no effect on glycine sensitivity, but reduced maximal currents in α1β GlyRs in both homozygous (α1βW310C) and heterozygous (α1ββW310C) 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.
Keyword GLRA1
Glycine receptor
Startle disease
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online: 10 December 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2013 Collection
School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 12 Feb 2013, 16:15:20 EST by Debra McMurtrie on behalf of Queensland Brain Institute