A FRAMESHIFT MUTATION IN THE MOUSE ALPHA(1) GLYCINE RECEPTOR GENE (GLRA1) RESULTS IN PROGRESSIVE NEUROLOGICAL SYMPTOMS AND JUVENILE DEATH

The neurologic mutant mouse, oscillator, is characterized by a fine mo tor tremor and muscle spasms that begin at 2 weeks of age and progress ively worsen, resulting in death by 3 weeks of age. We report the loca lization of the oscillator mutation to the central region of mouse Chr 11, and demonstrate its allelism with spasmodic, a recessive viable n eurological mutation which displays excessive startle. Oscillator is c aused by a microdeletion in the gene coding for the al subunit of the adult glycine receptor (Glra1). Glra1 assembles into a pentameric comp lex with the beta subunit of the glycine receptor (3 alpha(1)2 beta 5) to form a glycine-gated chloride channel. This receptor is the major adult glycine receptor, and the site of action of the poison strychnin e. The oscillator deletion causes a frameshift resulting in loss of th e highly conserved third cytoplasmic loop and fourth transmembrane dom ain of the protein. Membranes isolated from oscillator homozygote spin al cords display a 90% reduction in glycine-displaceable strychnine bi nding. This lack of ligand binding function confirms that oscillator i s a complete loss of function allele. The oscillator mutation provides evidence that although at least four different alpha subunits exist f or the glycine receptor, none of the other subunits can compensate for the loss of alpha(1), function. Mutations which impair GLRA1 function in humans have been shown to cause dominant familial startle disease. The identification of the oscillator mutation suggests that severe lo ss of function alleles in humans would result in prenatal or neonatal lethality.