| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Mullins, Jonathan G. L. Graham, Gail E. Matta, Stephanie Wood, Sian-elin Vanbellinghen, Jean-françois Born, Alfred P. Jones, Elizabeth A. Krause, Amanda Chatfield, Sue Keramidas, Angelo Thomas, Rhys H. Howell, Owain W. Kara, Bulent Vincent-delorme, Catherine Bartsch, Marius Freilinger, Michael Chung, Seo-kyung Hobson, Emma Lynch, Joseph W. Jain, Vivek Rahme, Jubran E. Karam, Elie G. Berkovic, Samuel F. Rees, Mark I. Bannasch, Gerald Cushion, Thomas D. Vassallo, Grace Aharoni, Sharon Drew, Cheney J. G. Alehan, Fusun Afawi, Zaid Pickrell, William O. Mandel, Hanna Bode, Anna Masri, Amira |
| Description |
Author Affiliation: Bode A ( From the University of Queensland, Queensland Brain Institute and School of Biomedical Sciences, Queensland 4072, Australia.) |
| Abstract |
Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month of life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with a definitive and clinically well stratified linkage to hyperekplexia. Most hyperekplexia cases are caused by mutations in the 1 subunit of the human glycine receptor (hGlyR) gene (GLRA1). Here we analyzed 68 new unrelated hyperekplexia probands for GLRA1 mutations and identified 19 mutations, of which 9 were novel. Electrophysiological analysis demonstrated that the dominant mutations p.Q226E, p.V280M, and p.R414H induced spontaneous channel activity, indicating that this is a recurring mechanism in hGlyR pathophysiology. p.Q226E, at the top of TM1, most likely induced tonic activation via an enhanced electrostatic attraction to p.R271 at the top of TM2, suggesting a structural mechanism for channel activation. Receptors incorporating p.P230S (which is heterozygous with p.R65W) desensitized much faster than wild type receptors and represent a new TM1 site capable of modulating desensitization. The recessive mutations p.R72C, p.R218W, p.L291P, p.D388A, and p.E375X precluded cell surface expression unless co-expressed with 1 wild type subunits. The recessive p.E375X mutation resulted in subunit truncation upstream of the TM4 domain. Surprisingly, on the basis of three independent assays, we were able to infer that p.E375X truncated subunits are incorporated into functional hGlyRs together with unmutated 1 or 1 plus ß subunits. These aberrant receptors exhibit significantly reduced glycine sensitivity. To our knowledge, this is the first suggestion that subunits lacking TM4 domains might be incorporated into functional pentameric ligand-gated ion channel receptors. |
| ISSN |
00219258 |
| e-ISSN |
1083351X |
| Journal |
Journal of Biological Chemistry |
| Issue Number |
47 |
| Volume Number |
288 |
| Language |
English |
| Publisher |
American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date |
2013-11-22 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Gene Expression Regulation Muscle Rigidity Metabolism Mutation, Missense Receptors, Glycine Amino Acid Substitution Genetics Protein Structure, Secondary Protein Structure, Tertiary Clinical Trial Multicenter Study Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Cell Biology Biochemistry Molecular Biology |
