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SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice

Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the vestibular labyrinth and the endolymphatic sac. Slc26a4 (Δ/Δ) mice are devo...

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Autores principales: Li, Xiangming, Sanneman, Joel D., Harbidge, Donald G., Zhou, Fei, Ito, Taku, Nelson, Raoul, Picard, Nicolas, Chambrey, Régine, Eladari, Dominique, Miesner, Tracy, Griffith, Andrew J., Marcus, Daniel C., Wangemann, Philine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708829/
https://www.ncbi.nlm.nih.gov/pubmed/23874234
http://dx.doi.org/10.1371/journal.pgen.1003641
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author Li, Xiangming
Sanneman, Joel D.
Harbidge, Donald G.
Zhou, Fei
Ito, Taku
Nelson, Raoul
Picard, Nicolas
Chambrey, Régine
Eladari, Dominique
Miesner, Tracy
Griffith, Andrew J.
Marcus, Daniel C.
Wangemann, Philine
author_facet Li, Xiangming
Sanneman, Joel D.
Harbidge, Donald G.
Zhou, Fei
Ito, Taku
Nelson, Raoul
Picard, Nicolas
Chambrey, Régine
Eladari, Dominique
Miesner, Tracy
Griffith, Andrew J.
Marcus, Daniel C.
Wangemann, Philine
author_sort Li, Xiangming
collection PubMed
description Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the vestibular labyrinth and the endolymphatic sac. Slc26a4 (Δ/Δ) mice are devoid of pendrin and develop a severe enlargement of the membranous labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4 (Δ/Δ) line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the vestibular labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy will restore normal hearing in human patients carrying a variety of mutations of SLC26A4.
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spelling pubmed-37088292013-07-19 SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice Li, Xiangming Sanneman, Joel D. Harbidge, Donald G. Zhou, Fei Ito, Taku Nelson, Raoul Picard, Nicolas Chambrey, Régine Eladari, Dominique Miesner, Tracy Griffith, Andrew J. Marcus, Daniel C. Wangemann, Philine PLoS Genet Research Article Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the vestibular labyrinth and the endolymphatic sac. Slc26a4 (Δ/Δ) mice are devoid of pendrin and develop a severe enlargement of the membranous labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4 (Δ/Δ) line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the vestibular labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy will restore normal hearing in human patients carrying a variety of mutations of SLC26A4. Public Library of Science 2013-07-11 /pmc/articles/PMC3708829/ /pubmed/23874234 http://dx.doi.org/10.1371/journal.pgen.1003641 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Li, Xiangming
Sanneman, Joel D.
Harbidge, Donald G.
Zhou, Fei
Ito, Taku
Nelson, Raoul
Picard, Nicolas
Chambrey, Régine
Eladari, Dominique
Miesner, Tracy
Griffith, Andrew J.
Marcus, Daniel C.
Wangemann, Philine
SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice
title SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice
title_full SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice
title_fullStr SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice
title_full_unstemmed SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice
title_short SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice
title_sort slc26a4 targeted to the endolymphatic sac rescues hearing and balance in slc26a4 mutant mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708829/
https://www.ncbi.nlm.nih.gov/pubmed/23874234
http://dx.doi.org/10.1371/journal.pgen.1003641
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