Low level of expression of known deafness genes Kcne1, Kcnj10 or Col4a3 is sufficient to maintain hearing in mice

Kcne1, Kcnj10 and Col4a3 are all expressed in the stria vascularis where they serve critical roles in generating the endocochlear potential. Mutations in any of these three genes are linked to human deafness syndromes for which there are currently no treatments. Here, the hearing ability of three mouse lines carrying mutant alleles in these genes ( Kcne1 tm1a , Kcnj10 tm1a and Col4a3 tm1a ) was investigated to assess whether they would develop an auditory phenotype similar to that of human patients. Surprisingly, all three mutant mice had normal hearing, at least up to 6 months of age, assessed by auditory brainstem response thresholds and waveforms and endocochlear potentials. Marginal cell arrangement in the stria vascularis was normal in Col4a3 tm1a/tm1a mice at 8 weeks of age but showed evidence of early cellular disorganisation in Kcnj10 tm1a/tm1a and Kcne1 tm1a/tm1a mice. We found that the Kcne1 tm1a , Kcnj10 tm1a and Col4a3 tm1a mutations led to incomplete knockdown of transcript, to 25% of normal values in each case, indicating these are hypomorphic alleles. These results suggest that partial restoration of KCNE1, KCNJ10 and COL4A3 expression in patients affected by mutations in these genes may be sufficient to preserve auditory function.