Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia

S K Chung; J F Vanbellinghen; J G L Mullins; A Robinson; J Hantke; C L Hammond; D F Gilbert; M Freilinger; M Ryan; M C Kruer; A Masri; C Gurses; C Ferrie; K Harvey; R Shiang; J Christodoulou; F Andermann; E Andermann; R H Thomas; Robert J Harvey; J W Lynch; M I Rees

doi:10.1523/JNEUROSCI.1763-10.2010

Back

Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia

Journal article

Open access

Peer reviewed

Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia

S K Chung, J F Vanbellinghen, J G L Mullins, A Robinson, J Hantke, C L Hammond, D F Gilbert, M Freilinger, M Ryan, M C Kruer, …

Journal of Neuroscience, Vol.30(28), pp.9612-9620

2010

DOI: https://doi.org/10.1523/JNEUROSCI.1763-10.2010

Files and links (2)

pdf

PDF - Published Version (Open Access)1.50 MBDownload View

Published VersionPDF - Published Version (Open Access)CC BY V3.0, Open Access

url

https://doi.org/10.1523/JNEUROSCI.1763-10.2010View

Published Version

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) α1 subunit (GLRA1) and the presynaptic glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of GLRA1in 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 α1 or heteromeric α1β 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. Copyright © 2010 the authors.

Details

Title: Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia
Authors: S K Chung (Author) - Swansea University, United Kingdom
J F Vanbellinghen (Author) - University of Liège, Belgium
J G L Mullins (Author) - Swansea University, United Kingdom
A Robinson (Author) - Swansea University, United Kingdom
J Hantke (Author) - University College London, United Kingdom
C L Hammond (Author) - Swansea University, United Kingdom
D F Gilbert (Author) - University of Queensland
M Freilinger (Author) - Medical University of Vienna, Austria
M Ryan (Author) - Murdoch Childrens Research Institute
M C Kruer (Author) - Oregon Health and Science University, United States
A Masri (Author) - University of Jordan, Jordan
C Gurses (Author) - Istanbul University, Turkey
C Ferrie (Author) - Leeds General Infirmary, United Kingdom
K Harvey (Author) - University College London, United Kingdom
R Shiang (Author) - Virginia Commonwealth University, United States
J Christodoulou (Author) - Alexandra Hospital for Children
F Andermann (Author) - McGill University, Canada
E Andermann (Author) - McGill University, Canada
R H Thomas (Author) - Swansea University, United Kingdom
Robert J Harvey (Author) - University College London, United Kingdom
J W Lynch (Author) - University of Queensland
M I Rees (Author) - Swansea University, United Kingdom
Publication details: Journal of Neuroscience, Vol.30(28), pp.9612-9620
Publisher: Society for Neuroscience (SFN)
Date published: 2010
DOI: 10.1523/JNEUROSCI.1763-10.2010
ISSN: 0270-6474
Copyright note: Copyright © 2010 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Organisation Unit: School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99451185502621
Output Type: Journal article

Metrics

7 File views/ downloads

475 Record Views

110 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Neurosciences

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites