Mutations in KCNQ1 and minK may cause deafness

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Expression of KCNQ1 and minK is not limited to the heart. Both are also expressed in the stria vascularis of the inner ear. This may explain why patients with recessive mutations in KCNQ1 (JLN syndrome) suffer from profound congenital deafness. Abnormalities in the C terminus of KCNQ1 have been found in some of these patients (Fig. 6.10). In two families, for example, a homozygous deletion of 7-bp and an 8-bp insertion at the same site was identified (Neyroud et al, 1997). This produced a frameshift at residue 415 and truncation of the protein close to the end of the normal coding region. A number of missense mutations have also been described (eg., W305S). The dominant negative effect of the JLN mutations is much less than that observed for the RW mutations, and correlates with the recessive mode of inheritance of JLN syndrome. Individuals homozygous for mutations in minK also suffer from deafness.

Why do recessive KCNQ1 and minK mutations lead to deafness? KCNQ1 is expressed in the marginal cells of the stria vascularis, that secrete the endolymph of the inner ear (Fig. 6.12). This is a K+ rich fluid that bathes the stereocilia of the sensory hair cells. A high endolymph K+ concentration is required for hair cell function. Lack of endolymph leads to death of the hair cells and degeneration of the ganglion cells in the auditory pathway, as is observed in mice in which the gene encoding minK (which modulates KCNQ1) has been knocked out. These animals also suffer hearing and balance

FIGURE 612 KCNQ1 IS EXPRESSED IN THE INNER EAR

Diagram of the inner ear showing the location of the marginal cells of the stria vascularis which express KCNQ1 and minK, and secrete the K+ rich endolymph. A reduction in the fluid that fills the endotic space results in the collapse of Reissner's membrane onto the sensory hair cells, and their subsequent degeneration.

The Role Stria Vascularis Hearing

Tectorial membrane

Stria vascularis

Reissner's membrane

Hair cells

FIGURE 612 KCNQ1 IS EXPRESSED IN THE INNER EAR

Diagram of the inner ear showing the location of the marginal cells of the stria vascularis which express KCNQ1 and minK, and secrete the K+ rich endolymph. A reduction in the fluid that fills the endotic space results in the collapse of Reissner's membrane onto the sensory hair cells, and their subsequent degeneration.

Tectorial membrane

Stria vascularis

Reissner's membrane

Hair cells defects, such as a defective righting reflex and circling behaviour (Vetter et al., 1996). The lack of KCNQ1 and minK may be expected to lead to a similar loss of endolymph K+ secretion and hair cell degeneration in man. Why some mutations should cause RW syndrome whereas others cause JLN syndrome has not been fully established.

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