Hereditary Deafness Newsletter
February 2000, No. 17
Professor Karen Steel*

One of the interesting observations emerging from the identification of more and more deafness genes in the human and mouse is the importance of the entire cochlear duct in auditory function. Many deafness genes seem to be involved in the process of ionic homeostasis in the cochlear duct, particularly the process of potassium recycling. During sound stimulation, potassium floods into the hair cells from the endolymph, and it needs to be removed and recycled. In outer hair cells, it is thought that the potassium channel encoded by KCNQ4 (involved in human non-syndromic deafness) may be involved in allowing potassium to leave. It is then taken up by underlying supporting cells and passed through a network of gap junctions that connect adjacent supporting cells and spiral ligament fibrocytes. The gap junctions are probably composed of connexins encoded by three genes, GJB2, GJB3, and GJB6, involved in non-syndromic deafness in humans. The transcription factor Pou3f4 is expressed in spiral ligament fibrocytes, and these fibrocytes show very limited cell-cell contacts in mice with the gene knocked out, a feature that might lead to limitation in potassium flow and the reduced endocochlear potentials measured in these mouse mutants. The human version of this gene, POU3F4, is affected in X-linked non-syndromic deafness in humans. The potassium is then pumped into the marginal cells of the stria vascularis by a Na-K-ATPase with the help of a Na-K-Cl cotransporter encoded by the Slc12a2 gene, and in three different mutations of this gene in the mouse, a failure in endolymph production has been observed resulting in collapse of Reissner's membrane. Once in the marginal cells, the potassium returns to the endolymph via a potassium channel formed of two components, encoded by the KCNQ1 (KvLQT1) and KCNE1 (IsK) genes, and either of these genes can be mutated in Jervell and Lange-Nielsen syndrome in humans. The IsK gene has been knocked out in the mouse, resulting in a failure in secretion of endolymph and collapse of Reissner's membrane. (References for these findings can be found at http://dnalab-www.uia.ac.be/dnalab/hhh or in Science 285:1363-1364, 1999).

The tectorial membrane has been implicated in hearing impairment in two recent papers. The COL11A2 gene was found to be mutated in non-syndromic and syndromic deafness, and the corresponding knockout mouse showed tectorial membrane defects (McGuirt et al. Nature Genetics 23:413-419, 1999). The tectorial membrane also showed ultrastructural defects associated with hearing impairment in the otogelin (Otog) knockout mouse (Simmler et al. Nature Genetics 24:139-143, 2000). Earlier, mutations in TECTA, encoding a tectorial membrane component, were described in non-syndromic deafness in humans.

These reports emphasize the importance of the entire cochlear duct in facilitating sensory hair cell function.

Reproduced with permission.

*MRC Institute of Hearing Research
University Park
Nottingham NG7 2RD, UK