Journal Article

Hyperekplexia associated with compound heterozygote mutations in the β-subunit of the human inhibitory glycine receptor (<i>GLRB</i>)

Mark I. Rees, Trevor M. Lewis, John B. J. Kwok, Geert R. Mortier, Paul Govaert, Russell G. Snell, Peter R. Schofield and Michael J. Owen

in Human Molecular Genetics

Volume 11, issue 7, pages 853-860
Published in print April 2002 | ISSN: 0964-6906
Published online April 2002 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/11.7.853
Hyperekplexia associated with compound heterozygote mutations in the β-subunit of the human inhibitory glycine receptor (GLRB)

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Hyperekplexia (MIM: 149400) is a neurological disorder characterized by an excessive startle response which can be caused by mutations in the α1-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 β-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 β-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 α1β (G229D) GlyR suggesting that GlyR β‐subunits are not restricted to conferring modulatory influences and maintaining structural integrity, but may also play a functional role in hGlyR ligand binding.

Journal Article.  6465 words.  Illustrated.

Subjects: Genetics and Genomics

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