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Endolymphatic Na? and K? concentrations during cochlear growth and enlargement in mice lacking Slc26a4/pendrin.

ABSTRACT: Slc26a4 (?/?) mice are deaf, develop an enlarged membranous labyrinth, and thereby largely resemble the human phenotype where mutations of SLC26A4 cause an enlarged vestibular aqueduct and sensorineural hearing loss. The enlargement is likely caused by abnormal ion and fluid transport during the time of embryonic development, however, neither the mechanisms of ion transport nor the ionic composition of the luminal fluid during this time of development are known. Here we determine the ionic composition of inner ear fluids at the time at which the enlargement develops and the onset of expression of selected ion transporters. Concentrations of Na(+) and K(+) were measured with double-barreled ion-selective electrodes in the cochlea and the endolymphatic sac of Slc26a4 (?/+), which develop normal hearing, and of Slc26a4 (?/?) mice, which fail to develop hearing. The expression of specific ion transporters was examined by quantitative RT-PCR and immunohistochemistry. High Na(+) (?141 mM) and low K(+) concentrations (?11 mM) were found at embryonic day (E) 16.5 in cochlear endolymph of Slc26a4 (?/+) and Slc26a4 (?/?) mice. Shortly before birth the K(+) concentration began to rise. Immediately after birth (postnatal day 0), the Na(+) and K(+) concentrations in cochlear endolymph were each ?80 mM. In Slc26a4 (?/?) mice, the rise in the K(+) concentration occurred with a ?3 day delay. K(+) concentrations were also found to be low (?15 mM) in the embryonic endolymphatic sac. The onset of expression of the K(+) channel KCNQ1 and the Na(+)/2Cl(-)/K(+) cotransporter SLC12A2 occurred in the cochlea at E19.5 in Slc26a4 (?/+) and Slc26a4 (?/?) mice. These data demonstrate that endolymph, at the time at which the enlargement develops, is a Na(+)-rich fluid, which transitions into a K(+)-rich fluid before birth. The data suggest that the endolymphatic enlargement caused by a loss of Slc26a4 is a consequence of disrupted Na(+) transport.

SUBMITTER: Li X

PROVIDER: S-EPMC3669272 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Endolymphatic Na⁺ and K⁺ concentrations during cochlear growth and enlargement in mice lacking Slc26a4/pendrin.

Li Xiangming X Zhou Fei F Zhou Fei F Marcus Daniel C DC Wangemann Philine P

PloS one 20130531 5

Slc26a4 (Δ/Δ) mice are deaf, develop an enlarged membranous labyrinth, and thereby largely resemble the human phenotype where mutations of SLC26A4 cause an enlarged vestibular aqueduct and sensorineural hearing loss. The enlargement is likely caused by abnormal ion and fluid transport during the time of embryonic development, however, neither the mechanisms of ion transport nor the ionic composition of the luminal fluid during this time of development are known. Here we determine the ionic compo ...[more]

PMID: 23741519

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Project description:BACKGROUND:Mutations in the SLC26A4 gene are associated with Pendred syndrome and autosomal recessive non-syndromic deafness (DFNB4). Both disorders have similar audiologic characteristics: bilateral hearing loss, often severe or profound, which may be associated with abnormalities of the inner ear, such as dilatation of the vestibular aqueduct or Mondini dysplasia. But, in Pendred syndrome (OMIM #274600), with autosomal recessive inheritance, besides congenital sensorineural deafness, goiter or thyroid dysfunctions are frequently present. The aim of this study was to determine whether mutations in SLC26A4 are a frequent cause of hereditary deafness in Brazilian patients. METHODS:Microsatellite haplotypes linked to SLC26A4 were investigated in 68 families presenting autosomal recessive non-syndromic deafness. In the probands of the 16 families presenting segregation consistent with linkage to SLC26A4, Sanger sequencing of the 20 coding exons was performed. In an additional sample of 15 individuals with suspected Pendred syndrome, because of the presence of hypothyroidism or cochleovestibular malformations, the SLC26A4 gene coding region was also sequenced. RESULTS:In two of the 16 families with indication of linkage to SLC26A4, the probands were found to be compound heterozygotes for probably pathogenic different mutations: three novel (c.1003 T?>?G (p. F335 V), c.1553G?>?A (p.W518X), c.2235?+?2 T?>?C (IVS19?+?2 T?>?C), and one already described, c.84C?>?A (p.S28R). Two of the 15 individuals with suspected Pendred syndrome because of hypothyreoidism or cochleovestibular malformations were monoallelic for likely pathogenic mutations: a splice mutation (IVS7?+?2 T?>?C) and the previously described c.1246A?>?C (p.T416P). Pathogenic copy number variations were excluded in the monoallelic cases and in those with normal results after Sanger sequencing. Additional mutations in the SLC26A4 gene or other definite molecular cause for deafness were not identified in the monoallelic patients, after exome sequencing. CONCLUSIONS:Biallelic pathogenic mutations in SLC26A4 explained ~?3% of cases selected because of autosomal recessive deafness. Monoallelic mutations were present in ~?13% of isolated cases of deafness with cochleovestibular malformations or suspected Pendred syndrome. These data reinforce the importance of mutation screening of SLC26A4 in Brazilian subjects and highlight the elevated frequency of monoallelic patients.

Dataset Information

Endolymphatic Na? and K? concentrations during cochlear growth and enlargement in mice lacking Slc26a4/pendrin.

Publications

Endolymphatic Na⁺ and K⁺ concentrations during cochlear growth and enlargement in mice lacking Slc26a4/pendrin.

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