New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms

Anna Bode, Sian-Elin Wood, Jonathan G L Mullins, Angelo Keramidas, Thomas D Cushion, Rhys H Thomas, William O Pickrell, Cheney J G Drew, Amira Masri, Elizabeth Ann Jones, Grace Vassallo, Alfred P Born, Fusun Alehan, Sharon Aharoni, Gerald Bannasch, Marius Bartsch, Bulent Kara, Amanda Krause, Elie G Karam, Stephanie MattaVivek Jain, Hanna Mandel, Michael Freilinger, Gail E Graham, Emma Hobson, Sue Chatfield, Catherine Vincent-Delorme, Jubran E Rahme, Zaid Afawi, Samuel F Berkovic, Owain W Howell, Jean-François Vanbellinghen, Mark I Rees, Seo-Kyung Chung, Joseph W Lynch

33 Citationer (Scopus)


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 α1 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 α1 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 α1 or α1 plus β 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.

TidsskriftJournal of Biological Chemistry
Udgave nummer47
Sider (fra-til)33745-59
Antal sider15
StatusUdgivet - 22 nov. 2013


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