UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Pathophysiological Mechanisms of Dominant and Recessive GLRA1 Mutations in Hyperekplexia

Chung, SK; Vanbellinghen, JF; Mullins, JGL; Robinson, A; Hantke, J; Hammond, CL; Gilbert, DF; ... Rees, MI; + view all (2010) Pathophysiological Mechanisms of Dominant and Recessive GLRA1 Mutations in Hyperekplexia. J NEUROSCI , 30 (28) 9612 - 9620. 10.1523/JNEUROSCI.1763-10.2010. Green open access

[thumbnail of pathophysiological._jon.pdf]
Preview
PDF
pathophysiological._jon.pdf
Available under License : See the attached licence file.

Download (1MB)

Abstract

Hyperekplexia is a rare, but potentially fatal, neuromotor disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden, unexpected auditory or tactile stimuli. This disorder is primarily caused by inherited mutations in the genes encoding the glycine receptor (GlyR) alpha 1 subunit (GLRA1) and the presynaptic glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of GLRA1 in 88 new unrelated human hyperekplexia patients revealed 19 sequence variants in 30 index cases, of which 21 cases were inherited in recessive or compound heterozygote modes. This indicates that recessive hyperekplexia is far more prevalent than previous estimates. From the 19 GLRA1 sequence variants, we have investigated the functional effects of 11 novel and 2 recurrent mutations. The expression levels and functional properties of these hyperekplexia mutants were analyzed using a high-content imaging system and patch-clamp electrophysiology. When expressed in HEK293 cells, either as homomeric alpha 1 or heteromeric alpha 1 beta GlyRs, subcellular localization defects were the major mechanism underlying recessive mutations. However, mutants without trafficking defects typically showed alterations in the glycine sensitivity suggestive of disrupted receptor function. This study also reports the first hyperekplexia mutation associated with a GlyR leak conductance, suggesting tonic channel opening as a new mechanism in neuronal ligand-gated ion channels.

Type: Article
Title: Pathophysiological Mechanisms of Dominant and Recessive GLRA1 Mutations in Hyperekplexia
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.1763-10.2010
Publisher version: http://www.jneurosci.org/content/30/28/9612.full
Language: English
Additional information: Copyright © 2010 the authors
Keywords: INHIBITORY GLYCINE RECEPTOR, BETA-SUBUNIT, COMPOUND HETEROZYGOSITY, ACETYLCHOLINE-RECEPTOR, TRANSMEMBRANE DOMAIN, CHLORIDE CHANNELS, MASS-SPECTROMETRY, STARTLE DISEASE, ALPHA-1 SUBUNIT, BINDING
UCL classification: UCL
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 Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1350607
Downloads since deposit
118Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item