title: The frameshift mutation oscillator (Glra1(spd-ot)) produces a complete loss of glycine receptor alpha1-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 alpha1-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 alpha1-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-alpha1 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 disparate regulation of glycine receptor subunit genes and/or diverse compensatory pathways in mice and humans.
authors.affiliation: Institut für Biochemie, Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kling
authors.forename: M
authors.initials: M
authors.lastname: Koch
authors.forename: B
authors.initials: B
authors.lastname: Saul
authors.forename: C M
authors.initials: CM
authors.lastname: Becker
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002490:Central Nervous System / Q000378:metabolism*; D005260:Female; D016368:Frameshift Mutation / Q000502:physiology*; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008818:Mice, Neurologic Mutants; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D018009:Receptors, Glycine / Q000096:biosynthesis / Q000235:genetics*; D013216:Reflex, Startle / Q000502:physiology; D013331:Strychnine / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D018009:Receptors, Glycine; D013331:Strychnine