Loss of cochlear HCO^sub 3^-secretion causes deafness via endolymphatic acidification and inhibition of Ca^sup 2+^ reabsorption in a Pendred syndrome mouse model

Pendred syndrome, characterized by childhood deafness and postpuberty goiter, is caused by mutations of SLC26A4, which codes for the anion exchanger pendrin. The goal of the present study was to determine how loss of pendrin leads to hair cell degeneration and deafness. We evaluated pendrin function...

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Bibliographic Details
Published in:American journal of physiology. Renal physiology 2007-05, Vol.292 (5), p.F1345
Main Authors: Wangemann, Philine, Nakaya, Kazuhiro, Wu, Tao, Maganti, Rajanikanth J
Format: Article
Language:English
Subjects:
Biochemistry
Body fluids
Deafness
Gene expression
Genetic disorders
Hair
Proteins
Rodents
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Summary:Pendred syndrome, characterized by childhood deafness and postpuberty goiter, is caused by mutations of SLC26A4, which codes for the anion exchanger pendrin. The goal of the present study was to determine how loss of pendrin leads to hair cell degeneration and deafness. We evaluated pendrin function by ratiometric microfluorometry, hearing by auditory brain stem recordings, and expression of K+ and Ca... channels by confocal immunohistochemistry. Cochlear pH and Ca... concentrations and endocochlear potential (EP) were measured with double-barreled ion-selective microelectrodes. Pendrin in the cochlea was characterized as a formate-permeable and DIDS-sensitive anion exchanger that is likely to mediate HCO...-secretion into endolymph. Hence endolymph in ... mice was more alkaline than perilymph, and the loss of pendrin in ... mice led to an acidification of endolymph. The stria vascularis of ... mice expressed the K+ channel Kcnj10 and generated a small endocochlear potential before the normal onset of hearing at postnatal day 12. This small potential and the expression of Kcnj10 were lost during further development, and ... mice did not acquire hearing. Endolymphatic acidification may be responsible for inhibition of Ca... reabsorption from endolymph via the acid-sensitive epithelial Ca... channels Trpv5 and Trpv6. Hence the endolymphatic Ca... concentration was found elevated in ... mice. This elevation may inhibit sensory transduction necessary for hearing and promote the degeneration of the sensory hair cells. Degeneration of the hair cells closes a window of opportunity to restore the normal development of hearing in ... mice and possibly human patients suffering from Pendred syndrome. (ProQuest-CSA LLC: ... denotes formulae/symbols omitted.)
ISSN:1931-857X
1522-1466