Elsevier

Neurobiology of Disease

Volume 52, April 2013, Pages 137-149
Neurobiology of Disease

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

https://doi.org/10.1016/j.nbd.2012.12.001Get rights and content
Under a Creative Commons license
open access

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.

Highlights

► We report novel missense mutations in the GlyR β subunit gene causing startle disease. ► Mutation M177R in the extracellular domain decreases GlyR agonist affinity. ► Mutation L285R in TM2 produces spontaneously active channels. ► Mutation W310C in TM3 affects hydrophobic stacking and shows incomplete dominance. ► Mutations in GLRB have unique pathogenic mechanisms and modes of inheritance.

Keywords

GLRA1
GLRB
Glycine receptor
Hyperekplexia
Startle disease

Cited by (0)

1

These authors contributed equally to this work.