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Functional characterization of compound heterozygosity for GlyR alpha 1 mutations in the startle disease hyperekplexia

Rea, R; Tijssen, MA; Herd, C; Frants, RR; Kullmann, DM; (2002) Functional characterization of compound heterozygosity for GlyR alpha 1 mutations in the startle disease hyperekplexia. EUR J NEUROSCI , 16 (2) 186 - 196. 10.1046/j.1460-9568.2002.02054.x.

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Abstract

The human disease hyperekplexia is characterized by excessive startle reactions to auditory and cutaneous stimuli. In its familial form, hyperekplexia has been associated with both dominant and recessive mutations of the GLRA1 gene encoding the glycine receptor alpha(1) subunit (GlyRalpha1), which mediates inhibitory transmission in the spinal cord and brainstem. Here we have examined the functional consequences of two amino acid substitutions found in a compound heterozygous family, R252H and R392H, to investigate the mechanisms determining this inheritance pattern. When expressed in Xenopus laevis oocytes, both mutations were non-functional. Neither mutant affected the electrophysiological properties of wild type GlyRalpha1 when co-expressed. We introduced a green fluorescent protein tag to mutant subunits and found that both mutant proteins were detectable. Evidence that subcellular localization differed from wild type was significant for one of the mutants. Thus, an effective loss of functional GlyRalpha1-mediated current underlies hyperekplexia in this family, whereas a partial loss is asymptomatic.

Type: Article
Title: Functional characterization of compound heterozygosity for GlyR alpha 1 mutations in the startle disease hyperekplexia
DOI: 10.1046/j.1460-9568.2002.02054.x
Keywords: glycine receptor, human channelopathy, INHIBITORY GLYCINE-RECEPTOR, RAT SPINAL-CORD, HEREDITARY HYPEREKPLEXIA, SPORADIC HYPEREKPLEXIA, ENDOPLASMIC-RETICULUM, BETA SUBUNIT, GENE GLRA1, PROTEIN, GEPHYRIN, CHANNEL
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
URI: http://discovery.ucl.ac.uk/id/eprint/113048
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