Deafness and imbalance associated with inactivation of the secretory Ma-K-2Cl co-transporter

Deaf ness can result from a variety of gene defects'. Some genes involved i n the physiology of hearing encode membrane transporters that regulate the ionic composition of the fluid bathing the inner ear. The endolymph is an e xtracellular fluid with an atypical composition that resembles the intracel lular milieu, high in K+ and low in Na+. Recent studies have emphasized the prominent role of K+ channels in endolymph secretion(2-4) and mechanical t ransduction(5). Coupled electroneutral transport of Na+, K+ and Cl- is: med iated by two isoforms of the. Na-K-2Cl cotransporter:the absorptive isoform BSC1 (also called NKCC2, encoded by SIc12a1 in mouse) that is exclusively expressed in kidney;- and BSC2/NKCC1 (encoded by SIc12a2 in mouse).: the se cretory isoform which has a wider pattern of expression including epithelia , muscle cells; neurons, and red blood cells(6,7). These Eo-transporters: s hare 57% homology at the amino acid level(8-11) and are pharmacologically i nhibited by loop diuretics. There is functional(12-14) and histochemical(15 -17) evidence for the presence of the secretory isoform of the Na-K-2Cl co- transporter in gerbil. rat and rabbit inner ear. We disrupted mouse SIc12a2 and report here that SIc12a2(-/-) mice are deaf and exhibit classic shaker /waltzer behaviour, indicative of inner-ear defects. We localized the co-tr ansporter to key secreting epithelia of the mouse inner ear and-show that a bsence of functional co-transporter leads to structural damages in the inne r ear consistent with a decrease in endolymph secretion.