Homozygotic spasmodic (spdlspd) mice suffer from a motor disorder resembling poisoning by the glycine receptor antagonist strychnine. Here, a point mutation was identified in the glycine receptor al subunit gene of the spasmodic mouse which predicts an alanine-to-serine exchange at position 52 of the mature polypeptide. Upon expression in Xenopus Iaevis oocytes, al As2s receptor channels displayed reduced responses to glycine, /I-alanine and taurine when compared to recombinant ccl glycine receptors. As glycine receptor content in spinal cord and native molecular weight appeared unaltered, this suggests that the spasmodic phenotype results from an altered neurotransmitter sensitivity of the mutant alAszs subunit.
Mutations in inhibitory glycine receptor (GlyR) subunit genes are associated with neuromotor diseases in man and mouse. To use the potential of the mouse mutants as animal models of human disease, we altered GlyR levels in mutant mice and studied their phenotype. A transgene coding for the beta subunit of the rat GlyR was introduced into the genetic background of the spa mutation, which is characterized by low endogenous expression levels of the beta subunit and a dramatic neuromotor phenotype. The resulting transgenic mice expressed the beta subunit mRNA at intermediate levels, and their phenotype was rescued. This provides formal proof for the casual relationship between GlyR beta gene mutation and motor disease, and indicates that a low level of beta gene expression (25% of normal) is sufficient for proper functioning of glycinergic synapses.
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