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

摘要: Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with definitive clinically well stratified linkage to hyperekplexia. Most hyperekplexia cases caused by mutations in α1 subunit human receptor (hGlyR) gene (GLRA1). Here we analyzed 68 new unrelated probands for GLRA1 identified 19 mutations, which 9 were novel. Electrophysiological analysis demonstrated dominant p.Q226E, p.V280M, p.R414H induced spontaneous channel activity, indicating this recurring mechanism hGlyR pathophysiology. at top TM1, most likely tonic activation via an enhanced electrostatic attraction p.R271 TM2, suggesting structural activation. Receptors incorporating p.P230S (which heterozygous p.R65W) desensitized much faster than wild type represent TM1 site capable modulating desensitization. The recessive p.R72C, p.R218W, p.L291P, p.D388A, p.E375X precluded cell surface expression unless co-expressed subunits. mutation resulted truncation upstream TM4 domain. Surprisingly, on basis three independent assays, able infer truncated subunits incorporated into functional hGlyRs together unmutated or plus β These aberrant exhibit significantly reduced sensitivity. To our knowledge, suggestion lacking domains might be receptors.