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Next Article 
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
Sobetzko1, 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 1P250T 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
Ki 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
Copyright © 1999 Society for Neuroscience 0270-6474/99/193869-09$05.00/0
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