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

Mutations in the human KCNQ4 gene were recently found by Kubisch et al. [Ce ll 96 (1999) 437-446] to cause a non-syndromic, autosomal dominant, progres sive hearing loss, DFNA2. The mouse Kcnq4 orthologue was previously localiz ed to the outer hair cells (OHCs) of the inner ear, suggesting the pathophy siological effects were due to dysfunctional OHCs. Yet, OHC dysfunction doe s not provide a plausible explanation for the progressive nature of the fre quency specific hearing loss. We have re-examined and extended the expressi on analyses of KCNQ4 in the murine inner ear using RT-PCR and whole mount i n situ hybridization. Our results confirmed that the rat KCNQ4 orthologue i s expressed in both inner and outer hair cells. Reciprocal longitudinal gra dients were found in inner hair cells (IHCs) and OHCs. The strongest expres sion of KCNQ4 in IHCc was in the base of the cochlea and in the apex for OH Cs. Similar to the IHCs, a basal to apical gradient was present in the spir al 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 heari ng loss. Our data suggest that the primary defect leading to initial high f requency loss and subsequent progressive hearing loss for all frequencies m ay be due to spiral ganglion and/or IHC dysfunction, rather than an OHC abe rration. (C) 2000 Elsevier Science B.V. All rights reserved.