A GLRA1 NULL MUTATION IN RECESSIVE HYPEREKPLEXIA CHALLENGES THE FUNCTIONAL-ROLE OF GLYCINE RECEPTORS

Dominant missense mutations in the human glycine receptor (GlyR) alpha 1 subunit gene (GLRA1) give rise to hereditary hyperekplexia. These m utations impair agonist affinities and change conductance states of ex pressed mutant channels, resulting in a partial loss of function. In a recessive case of hyperekplexia, we found a deletion of exons 1-6 of the GLRA1 gene. Born to consanguineous parents, the affected child is homozygous for this GLRA1(null) allele consistent with a complete loss of gene function. The child displayed exaggerated startle responses a nd pronounced head-retraction jerks reflecting a disinhibition of vest igial brain-stem reflexes. In contrast, proprio- and exteroceptive inh ibition of muscle activity previously correlated to glycinergic mechan isms were not affected. This case demonstrates that, in contrast to th e lethal effect of a null allele in the recessive mouse mutant oscilla tor (Glra1(spd-ot)), the loss of the GLyR alpha 1 subunit is effective ly compensated in man.