Human Molecular Genetics, 2002, Vol. 11, No. 7 853-860
© 2002 Oxford University Press
Hyperekplexia associated with compound heterozygote mutations in the ß-subunit of the human inhibitory glycine receptor (GLRB)
1Department of Psychological Medicine and 2Department of Medical Genetics, University of Wales College of Medicine, Cardiff CF14 4XN, UK, 3The Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia, 4Department of Medical Genetics and 5Department of Paediatrics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium and 6Department of Molecular Medicine, University of Auckland Medical School, Private Bag 92019, Auckland, New Zealand
Hyperekplexia (MIM: 149400) is a neurological disorder characterized by an excessive startle response which can be caused by mutations in the 
1-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 ß-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 ß-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+5GA results in the exclusion of exon 5 from GLRB transcripts. Electrophysiological studies showed reduced sensitivity to agonist mediated activation of the 1ß (G229D) GlyR suggesting that GlyR ß-subunits are not restricted to conferring modulatory influences and maintaining structural integrity, but may also play a functional role in hGlyR ligand binding.
+ To whom correspondence should be addressed at: Neuropsychiatric Genetics Unit, Tenovus Building, University of Wales College of Medicine, Cardiff, CF14 4XN, UK. Tel: +44 02920 743058; Fax: +44 02920 746554; Email : owenmj@cardiff.ac.uk
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