A frameshift mutation in the mouse α1 glycine receptor gene (Gira1) results in progressive neurological symptoms and juvenile death

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Abstract
The neurologic mutant mouse, oscillator, Is characterized by a fine motor tremor and muscle spasms that begin at 2 weeks of age and progressively worsen, resulting in death by 3 weeks of age. We report the localization of the oscillator mutation to the central region of mouse Chr 11, and demonstrate its allelism with spasmodic, a recessive viable neurological mutation which displays excessive startle. Oscillator Is caused by a microdeletion In the gene coding for the α1 subunit of the adult glyclne receptor (Glra1). Glra1 assembles into a pentameric complex with the β subunit of the glycine receptor (3α12β 5) to form a glycine-gated chloride channel. This receptor is the major adult glycine receptor, and the site of action of the poison strychnine. The oscillator deletion causes a frameshift resulting in loss of the highly conserved third cytoplasmlc loop and fourth transmembrane domain of the protein. Membranes Isolated from oscillator homozygote spinal cords display a 90% reduction in glycine-displaceable strychnine binding. This lack of ligand binding function confirms that oscillator is a complete loss of function allele. The oscillator mutation provides evidence that although at least four different α subunits exist for the glycine receptor, none of the other subunits can compensate for the loss of α1 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 loss of function alleles in humans would result in prenatal or neonatal lethality.

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