Journal article
Novel missense mutations in the glycine receptor β subunit gene (GLRB) in startle disease
Neurobiology of Disease, Vol.52, pp.137-149
2013
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. © 2012 Elsevier Inc.
Details
- Title
- Novel missense mutations in the glycine receptor β subunit gene (GLRB) in startle disease
- Authors
- V M James (Author) - University College London, United KingdomA Bode (Author) - University of QueenslandS K Chung (Author) - Swansea University, United KingdomJ L Gill (Author) - University College London, United KingdomM Nielsen (Author) - Leiden University Medical Center, NetherlandsF M Cowan (Author) - Imperial College London, United KingdomM Vujic (Author) - Imperial College London, United KingdomR H Thomas (Author) - Swansea University, United KingdomM I Rees (Author) - Swansea University, United KingdomK Harvey (Author) - University College London, United KingdomA Keramidas (Author) - University of QueenslandM Topf (Author) - Birkbeck College, United KingdomI Ginjaar (Author) - Leiden University Medical Center, NetherlandsJ W Lynch (Author) - University of QueenslandRobert J Harvey (Author) - University College London, United Kingdom
- Publication details
- Neurobiology of Disease, Vol.52, pp.137-149
- Publisher
- Academic Press
- Date published
- 2013
- DOI
- 10.1016/j.nbd.2012.12.001
- ISSN
- 0969-9961
- Copyright note
- Copyright © James et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 License.
- Organisation Unit
- School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99451018802621
- Output Type
- Journal article
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