Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia.
Chung S, Vanbellinghen J, Mullins J, Robinson A, Hantke J, Hammond C, Gilbert D, Freilinger M, Ryan M, Kruer M, Masri A, Gurses C, Ferrie C, Harvey K, Shiang R, Christodoulou J, Andermann F, Andermann E, Thomas R, Harvey R, Lynch J, Rees M (2010)
Publication Language: English
Publication Status: Published
Publication Type: Journal article, Original article
Publication year: 2010
Journal
Publisher: Society for Neuroscience
Book Volume: 30
Pages Range: 9612-20
Journal Issue: 28
DOI: 10.1523/JNEUROSCI.1763-10.2010
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) alpha1 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 alpha1 or heteromeric alpha1beta 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.
Authors with CRIS profile
Involved external institutions
Swansea University
United Kingdom (GB)
University of Liège (ULg) / Université de Liège
Belgium (BE)
University College London (UCL)
United Kingdom (GB)
Medizinische Universität Wien
Austria (AT)
Royal Children's Hospital Parkville
Australia (AU)
Oregon Health and Science University (OSHU)
United States (USA) (US)
University of Jordan
Jordan (JO)
Istanbul University / İstanbul Üniversitesi
Turkey (TR)
Leeds General Infirmary
United Kingdom (GB)
Virginia Commonwealth University (VCU)
United States (USA) (US)
Western Sydney Genetics Program, Children's Hospital
Australia (AU)
McGill University
Canada (CA)
University of Queensland
Australia (AU)
United Kingdom (GB)
University of Liège (ULg) / Université de Liège
Belgium (BE)
University College London (UCL)
United Kingdom (GB)
Medizinische Universität Wien
Austria (AT)
Royal Children's Hospital Parkville
Australia (AU)
Oregon Health and Science University (OSHU)
United States (USA) (US)
University of Jordan
Jordan (JO)
Istanbul University / İstanbul Üniversitesi
Turkey (TR)
Leeds General Infirmary
United Kingdom (GB)
Virginia Commonwealth University (VCU)
United States (USA) (US)
Western Sydney Genetics Program, Children's Hospital
Australia (AU)
McGill University
Canada (CA)
University of Queensland
Australia (AU)
How to cite
APA:
Chung, S., Vanbellinghen, J., Mullins, J., Robinson, A., Hantke, J., Hammond, C.,... Rees, M. (2010). Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia. The Journal of Neuroscience, 30(28), 9612-20. https://dx.doi.org/10.1523/JNEUROSCI.1763-10.2010
MLA:
Chung, SK, et al. "Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia." The Journal of Neuroscience 30.28 (2010): 9612-20.
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