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

F55 The Identification of a Candidate Gene for the wi Deafness Mutant

A. Varela1, P. Mburu1, R. E. Hardisty1, H. T. Tsai1, A. J. W. Paige1, B. W. Kiernan2, R. H. Holme2, J. Fleming2, M. J. C. Rogers2, K. P. Steel2 and S. D. M. Brown1. MRC Mouse Genome Centre and Mammalian Genetics Unit, Harwell, Oxon, OX11 0RD, UK; 2MRC Institute of Hearing Research, University Park, Nottingham, NG7 2RD, UK

The whirler mutant was discovered by P.W Lane (1963) as a spontaneous circling, head tossing and deaf mouse. Homozygous mice have a defect in the specialised neuroepithelium of the inner ear, the organ of Corti. The stereocilia at the apical surface of the inner hair cells are shorter than in wild type animals (Kiernan et al., unpublished observations).

Having completed a genetic and physical map of the whirler region on mouse chromosome 4 (Rogers et al., 1999, Mammalian Genome 10, 513-519 and unpublished data) a minimal tiling pathway of three BACs has been established which completely encompasses the whirler non-recombinant region. Using a combination of gene hunting techniques such as exon trapping, cDNA selection and BAC transgenesis we have isolated several candidate genes. One of the BACs from the minimal tiling pathway rescues the whirler phenotype allowing us to further refine the whirler locus interval. One novel candidate gene that lies within this interval shows substantially reduced levels of transcript in mutant whirler mice and demonstrates a very provocative expression pattern. Radioactive in-situ hybridisation on inner ear sections shows candidate gene expression in the inner sulcus and spiral limbus of the cochlear duct as well as the bony capsule. Antibodies raised against the putative whirler protein have demonstrated localisation to Hensen's stripe, Hardesty's membrane and the basal layer of the tectorial membrane on paraffin sections using DAB staining. The characterisation of this inner ear candidate gene may allow further dissection of novel components of the auditory pathway.


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