A GLRA1NullMutation inRecessive Hyperekplexia Challenges the Functional RoleofGlycine Receptors

Koin Summary Dominant missense mutations inthehumanglycine receptor (GlyR) alsubunit gene(GLRA1) give rise to hereditary hyperekplexia. These mutations impair agonist affinities andchange conductance states ofexpressed mutant channels, resulting inapartial loss of function. Inarecessive case ofhyperekplexia, wefound adeletion ofexons 1-6oftheGLRA1gene. Bornto consanguineous parents, theaffected child ishomozygousforthis GLRAln' allele consistent with acomplete loss ofgenefunction. Thechild displayed exaggerated startle responses andpronounced head-retraction jerks reflecting adisinhibition ofvestigial brain-stem reflexes. Incontrast, proprio- andexteroceptive inhibition of muscle activity previously correlated toglycinergic mechanisms werenotaffected. Thiscase demonstrates that, incontrast tothelethal effect ofanull allele inthe recessive mousemutant oscillator (Glrals'Pt), theloss oftheGlyRalsubunit iseffectively compensated in man.