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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.

Type Journal
ISBN 0964-6906 (Print)
Authors Rees, M. I.;Lewis, T. M.;Kwok, J. B.;Mortier, G. R.;Govaert, P.;Snell, R. G.;Schofield, P. R.;Owen, M. J. :
Published Date 2002-01-01
Published Volume 11
Published Issue 7
Published Pages 853-60
Status Published in-print
URL link to publisher's version