Longitudinal gradients of KCNQ4 expression in spiral ganglion and cochlear hair cells correlate with progressive hearing loss in DFNA2.

Mutations in the human KCNQ4 gene were recently found by Kubisch et al. [Cell 96 (1999) 437-446] to cause a non-syndromic, autosomal dominant, progressive hearing loss, DFNA2. The mouse Kcnq4 orthologue was previously localized to the outer hair cells (OHCs) of the inner ear, suggesting the pathophysiological effects were due to dysfunctional OHCs. Yet, OHC dysfunction does not provide a plausible explanation for the progressive nature of the frequency specific hearing loss. We have re-examined and extended the expression analyses of KCNQ4 in the murine inner ear using RT-PCR and whole mount in situ hybridization. Our results confirmed that the rat KCNQ4 orthologue is expressed in both inner and outer hair cells. Reciprocal longitudinal gradients were found in inner hair cells (IHCs) and OHCs. The strongest expression of KCNQ4 in IHCc was in the base of the cochlea and in the apex for OHCs. Similar to the IHCs, a basal to apical gradient was present in the spiral sensory neurons. IHCs mediate hearing via their afferent sensory neurons, whereas OHCs function as active cochlear amplifiers. The complete absence of OHCs leads only to severe sensitivity reduction, but not complete hearing loss. Our data suggest that the primary defect leading to initial high frequency loss and subsequent progressive hearing loss for all frequencies may be due to spiral ganglion and/or IHC dysfunction, rather than an OHC aberration.