Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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 Huw, 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 , pp. 137-149. 10.1016/j.nbd.2012.12.001

Full text not available from this repository.

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.

Item Type: Article
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords: GLRA1; GLRB; Glycine receptor; Hyperekplexia; Startle disease
Publisher: Elsevier
ISSN: 0969-9961
Last Modified: 04 Jun 2017 08:58
URI: http://orca.cf.ac.uk/id/eprint/88697

Citation Data

Cited 33 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item