The frameshift mutation oscillator ( Glra1 spd-ot) produces a complete loss of glycine receptor α1-polypeptide in mouse central nervous system

Abstract

Mice homozygous for the recessive mutation oscillator ( Glra1 spd-ot ) suffer from a complex motor disorder leading to death within three weeks after birth. Symptoms of this disorder mimic poisoning by strychnine, the antagonist of the inhibitory glycine receptor. The syndrome has previously been correlated to a 7 base pair microdeletion within the Glra1 gene (chromosome 11) encoding the α1-subunit of the adult glycine receptor isoform. As shown by [ 3H]strychnine binding and western blot analysis employing subunit-specific antibodies, spinal cord of homozygous oscillator mice was totally devoid of α1-polypeptide, characterizing the Glra1 spd-ot gene as a functional null allele of Glra1. Moreover, tissue levels of the postsynaptic anchoring protein gephyrin were drastically reduced in the Glra1 spd-ot/Glra1 spd-ot genotype. In contrast, immunoanalysis revealed a persisting low-level expression of non-α1 glycine receptor polypeptides. Spinal glycine receptor content was also significantly reduced in the +/Glra1 spd-ot genotype. This reduction coincided with increased acoustic startle responses in heterozygous animals consistent with haplotype insufficiency of glycine receptor function. Lethality of the murine null allele Glra1 spd-ot contrasts with the situation in the human, where homozygosity for a GLRA1 null allele produces the phenotype of the non-lethal disorder hyperekplexia (startle disease; stiff baby syndrome). This suggests a disperate regulation of glycine receptor subunit genes and/or diverse compensatory pathways in mice and humans.