title: Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB).
abstract: Hyperekplexia (MIM: 149400) is a neurological disorder characterized by an excessive startle response which can be caused by mutations in the alpha1-subunit (GLRA1) of the heteropentameric human inhibitory glycine receptor (hGlyR). These receptors facilitate fast-response, inhibitory glycinergic neurotransmission in the brainstem and spinal cord leading to a rapid modification and reduction of the excitatory startle response. Mutations in the beta-subunit of GlyR (glrb) occur in a murine model of hyperekplexia (spastic), but have not been detected in human hyperekplexia. Following mutation analysis of the human beta-subunit of hGlyR (GLRB) in a cohort of 22 hyperekplexia patients, we provide evidence to confirm that GLRB mutations can cause human hyperekplexia. A missense (G920A resulting in G229D) and a splice site mutation (IVS5+5G-->A) occurred together in a compound heterozygote with a transient hyperekplexia phenotype. Exon trap analysis revealed that IVS5+5G-->A results in the exclusion of exon 5 from GLRB transcripts. Electrophysiological studies showed reduced sensitivity to agonist mediated activation of the alpha1beta (G229D) GlyR suggesting that GlyR beta-subunits are not restricted to conferring modulatory influences and maintaining structural integrity, but may also play a functional role in hGlyR ligand binding.
authors.affiliation: Department of Psychological Medicine and Department of Medical Genetics, University of Wales College of Medicine, Cardiff CF14 4XN, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: Rees
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Lewis
authors.forename: John B J
authors.initials: JB
authors.lastname: Kwok
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
authors.forename: Paul
authors.initials: P
authors.lastname: Govaert
authors.forename: Russell G
authors.initials: RG
authors.lastname: Snell
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
mesh_terms: D002675:Child, Preschool; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics*; D022821:RNA Splice Sites; D018009:Receptors, Glycine / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C114561:GLRB protein, human; D022821:RNA Splice Sites; D018009:Receptors, Glycine