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The Journal of Neuroscience, February 1, 1999, 19(3):869-877

Novel GLRA1 Missense Mutation (P250T) in Dominant Hyperekplexia Defines an Intracellular Determinant of Glycine Receptor Channel Gating

Brigitta Saul¹, Thomas Kuner², Diana Sobetzko^{1, 4}, Wolfram Brune³, Folker Hanefeld⁴, Hans-Michael Meinck³, and Cord-Michael Becker¹

¹ Institut für Biochemie, Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany, ² Max-Planck-Institut für Medizinische Forschung, D-69120 Heidelberg, Germany, ³ Neurologische Klinik, Universität Heidelberg, D-69120 Heidelberg, Germany, and ⁴ Zentrum für Kinderheilkunde, Schwerpunkt Neuropädiatrie, Universität Göttingen, D-37075 Göttingen, Germany

Missense mutations as well as a null allele of the human glycine receptor 1 subunit gene GLRA1 result in the neurological disorder hyperekplexia [startle disease, stiff baby syndrome, Mendelian Inheritance in Man (MIM) #149400]. In a pedigree showing dominant transmission of hyperekplexia, we identified a novel point mutation C1128A of GLRA1. This mutation encodes an amino acid substitution (P250T) in the cytoplasmic loop linking transmembrane regions M1 and M2 of the mature 1 polypeptide. After recombinant expression, homomeric 1^P250T subunit channels showed a strong reduction of maximum whole-cell chloride currents and an altered desensitization, consistent with a prolonged recovery from desensitization. Apparent glycine binding was less affected, yielding an approximately fivefold increase in K_i values. Topological analysis predicts that the substitution of proline 250 leads to the loss of an angular polypeptide structure, thereby destabilizing open channel conformations. Thus, the novel GLRA1 mutant allele P250T defines an intracellular determinant of glycine receptor channel gating.

Key words: glycine; hyperekplexia; inhibition; receptor; startle disease; stiff baby syndrome

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Copyright © 1999 Society for Neuroscience  0270-6474/99/193869-09$05.00/0

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