| Abstract #35, Date 2/14/99, Session E1, Poster (J3) |
| Genetic and morphological analysis of pirouette: A mouse neuroepithelial deafness mutant |
| H. Odeh (Otolaryng., Kresge Hearing Res.Inst., Anatomy and Cell Biol.); L. Beyer, *K. Hunker, D.F. Dolan, Y. Raphael (Otolaryng., Kresge Hearing Res. Inst.); D.C. Kohrman (Otolaryng., Kresge Hearing Res.Inst., Human Gen., Univ. of Michigan Med. School) |
Early onset hearing loss and circling behavior in the mouse pirouette (pi) mutant are inherited as autosomal recessive traits with complete penetrance. The sensory epithelium in the cochlea of pirouette homozygotes undergoes a progressive degeneration, with cell loss beginning at approximately P21. Earlier analysis of surface preparations from the membranous labyrinth 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’), very similar to that found on IHC of another mouse deafness mutant, ‘shaker 2’ (Science 280:1444-1447, 1998). The early stereocilia deterioration and presence of actin cytocauds on IHC suggest a primary defect in the regulation of actin polymerization in pirouette. Very similar defects have been observed in shaker 2 mice, which carry mutations in Myo15, a gene encoding an unconventional myosin. The molecular defect in pirouette may therefore reside in a gene acting within the Myo15 pathway, or a related pathway required for appropriate regulation of actin filament formation in the inner ear. We are currently examining intracellular structures in greater detail using transmission electron microscopy. We have generated F2 mice from the cross (C57BL/6J-pi X CAST/Ei)F1 in order to construct a high resolution genetic map of the central region of chromosome 5 around the pi locus. Analysis of the products of over 1200 meioses indicates the pirouette gene is within a 0.2cM region proximal of Gabra2 and Gabrb1. Recc1 is located proximal of pi, indicating that the human pi gene is likely to reside within a 5Mb region flanked by RFCA/Recc1 and the GABA receptor subunit genes. We have constructed a nearly complete physical contig of the region using BAC and PAC genomic clones. We are assessing positional candidate genes, and further narrowing the candidate region using a transgene correction strategy to identify genomic clones which contain the gene affected in pirouette. |