Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB).
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.
Rees
Mark I
MI
Department of Psychological Medicine and Department of Medical Genetics, University of Wales College of Medicine, Cardiff CF14 4XN, UK.
Lewis
Trevor M
TM
Kwok
John B J
JB
Mortier
Geert R
GR
Govaert
Paul
P
Snell
Russell G
RG
Schofield
Peter R
PR
Owen
Michael J
MJ
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
C114561:GLRB protein, human; D022821:RNA Splice Sites; D018009:Receptors, Glycine