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

F1 Mutation of the Na-K-Cl Cotransporter Gene Slc12a2 in Shaker-with-Syndactylism Mutants

Karen P. Steel1, James Gazzard1, Shazia Chaudhry2, Natalie Sampson2, Bradley A. Schulte3, and Michael J Dixon2 . 1MRC Institute of Hearing Research, University Park, Nottingham NG7 2RD, UK; 2School of Biological Sciences and Department of Dental Medicine and Surgery, 3.239 Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK; 3 Department of Pathology and Laboratory Medicine and Department of Otolaryngology and Communicative Sciences, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA

Shaker-with-syndactylism (sy) is a radiation-induced, recessively-inherited mutation leading to syndactylism, deafness and balance defects, described first in the 1940s. Recently, Johnson et al. (Mamm. Genome 9:889, 1998) described a new deaf allele with no syndactyly, syns, and showed that the syndactylism and balance defects with deafness in sy were likely to be due to different genes in a contiguous gene deletion syndrome. Using a positional candidate approach, we have shown that the Slc12a2 gene (also known as Nkcc2 or mBSC2) is deleted in sy and carries an insertion of a single nucleotide (nt2955 insA) and predicted frameshift in the syns allele. Slc12a2 encodes a Na-K-Cl cotransporter expressed in the basolateral membranes of marginal cells of the stria vascularis, and the molecule is believed to act in concert with Na-K-ATPase to pump potassium into the marginal cells, from where it is passed into the endolymph which bathes the sensory hair cells of the cochlea. We have shown that there is a failure in secretion of endolymph in syns homozygotes, leading to collapse of the endolymphatic fluid compartments, and gross narrowing of the semicircular canals. This finding provides the molecular basis of another link in the chain of potassium recycling in the cochlea, a process essential for normal cochlear function.

 


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