International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F34 Progress in Genetic and Functional Characterization of Two Mouse Deafness Mutants, pirouette and spinner

David C. Kohrman1,2,3, Hana Odeh1,2 , Kristina Hunker1, Ellen Hibbard1, Lisa Beyer1, Gary Dootz1, Nobuko Hagiwara4, Murray H. Brilliant4, David F. Dolan1, and Yehoash Raphael1; 1Department of Otolaryngology/Kresge Hearing Research Institute; 2Department of Anatomy and Cell Biology; 3Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, U.S.A.; 4Department of Pediatrics, Health Sciences Center, University of Arizona, Tucson, AZ 85721, U.S.A.

The mouse mutants pirouette and spinner exhibit early onset hearing loss and circling behavior inherited as autosomal recessive traits. We have examined cochlear structure in affected homozygotes of both strains at adult and early postnatal time points. Both spinner and pirouette exhibited defects in hair cell morphology during postnatal development of the sensory neuroepithelium. Analysis of surface preparations from the membranous labyrinth by light and scanning electron microscopy indicated a progressive deterioration of stereocilia on inner and outer hair cells (IHC and OHC) in pirouette mice, beginning at approximately P5. Each IHC also exhibited a single actin-containing filament ('cytocaud'). Hair cell loss is first evident at approximately P21. The early stereocilia deterioration and presence of actin cytocauds on IHC suggest a primary defect in the regulation of actin polymerization in the hair cells of pirouette. Morphological analysis of homozygous spinner mice indicated a similar pattern and time course of progressive hair cell degeneration in the cochlea, with OHC loss first evident at approximately P25, followed by later IHC loss. The earliest defect we have identified is a slight abnormality in OHC stereocilia structure in the cochlea of P14 sr/sr mice, characterized by shortening or loss of a small number of stereocilia from OHC, usually at the outer perimeters of the bundles. By P25, all stereocilia on OHC are either missing or severely shortened.

We have analyzed F2 mice from intrasubspecific intercrosses segregating each of the mutations, and constructed high resolution genetic maps of the regions containing each locus. The pirouette locus is located within a 0.2 cM region proximal of Gabra2 and Gabrb1 on chromosome 5. Comparative mapping studies indicated the human ortholog of pirouette is likely to be located at 4p12-14, and suggests this gene as a positional candidate for the DFNB25 locus. Mutation at this locus results in recessively inherited, nonsyndromic deafness (R. Smith, unpublished data). Linkage analysis indicated the spinner locus is located 0.8 0.4 cM proximal of the Stac gene on chromosome 9, in a region of conserved synteny with human chromosome 3p21. DFNB6, another human deafness locus, has been previously localized to this region (Fukushima et al., 1995); the human spinner ortholog may therefore be a positional candidate gene for DFNB6.

We have assembled YAC, BAC and PAC physical contig maps across the nonrecombinant candidate regions for both spinner and pirouette, as starting points for positional cloning of each of the affected genes. In addition, we have identified a transgene insertional allele at the pirouette locus. The transgenic line fails to complement the spontaneous pirouette mutation, the insertion site has been genetically localized to central chromosome 5, and the abnormal cochlear morphology of homozygous transgenic mice is indistinguishable from that of homozygotes carrying the spontaneous mutation. We are currently screening genomic DNA flanking the transgenic insertion site for candidate exons.

Fukushima K, Ramesh A, Srisailapathy CRS, Ni L, Wayne S, O'Neill ME, Van Camp G, Coucke P, Jain P, Wilcox ER, Smith SD, Kenyon JB, Zbar RIS, Smith RJH: Genome Research 5:305-308, 1995.


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