Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia.

Beitrag in einer Fachzeitschrift
(Originalarbeit)


Details zur Publikation

Autor(en): 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
Zeitschrift: The Journal of Neuroscience
Verlag: Society for Neuroscience
Jahr der Veröffentlichung: 2010
Band: 30
Heftnummer: 28
Seitenbereich: 9612-20
ISSN: 1529-2401
Sprache: Englisch


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.



FAU-Autoren / FAU-Herausgeber

Gilbert, Daniel PD Dr.
Lehrstuhl für Medizinische Biotechnologie


Autor(en) der externen Einrichtung(en)
Istanbul University / İstanbul Üniversitesi
Leeds General Infirmary
McGill University
Medizinische Universität Wien
Oregon Health and Science University (OSHU)
Royal Children's Hospital Parkville
Swansea University
University College London (UCL) (University of London)
University of Jordan
University of Liège (ULg) / Université de Liège
University of Queensland
Virginia Commonwealth University
Western Sydney Genetics Program, Children's Hospital


Zitierweisen

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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Zuletzt aktualisiert 2018-09-08 um 23:15