Twister mutant mice are defective for otogelin, a component specific to inner ear acellular membranes

Deafness is a common sensory defect in human. Our understanding of the mole cular bases of this pathology comes from the study of a few genes that have been identified in human and/or in mice. Indeed, deaf mouse mutants are go od models for studying and identifying genes involved in human hereditary h earing loss. Among these mouse mutants, twister was initially reported to h ave abnormal behavior and thereafter to be deaf. The recessive twister (twt ) mutation has been mapped on mouse Chromosome (Chr) 7, homologous to the l ong arm of human Chr 15 (15q11). Otog, the gene encoding otogelin, a glycop rotein specific to all the acellular membranes of the inner ear, is also lo calized to mouse Chr 7, but in a region more proximal to the twister mutati on, homologous to the short arm of human Chr 11 (11p15) carrying the two de afness loci, DFNB 18 and USH1C. Mutant mice resulting from the knock out of Otog, the Otog(tm1Prs) mice, present deafness and severe imbalance. Althou gh twt had been mapped distally to Otog, these data prompted us to test whe ther twt could be due to a mutation in the Otog locus. Here, we demonstrate by genetic analysis that twt is actually allelic to Otog(tm1Prs). We furth er extend the phenotypical analysis of twister mice, documenting the associ ation of a severe vestibular phenotype and moderate to severe form of deafn ess. Molecular analysis of the Otog gene revealed the absence of detectable expression of Otog in the twister mutant. The molecular and phenotypical d escription of the twt mouse mutation, Otog(twt), reported herein, highlight s the importance of the acellular membranes in the inner ear mechanotransdu ction process.