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Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration

In vertebrates, 14-3-3 proteins form a family of seven highly conserved isoforms with chaperone activity, which bind phosphorylated substrates mostly involved in regulatory and checkpoint pathways. 14-3-3 proteins are the most abundant protein in the brain and are abundantly found in the cerebrospin...

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Autores principales: Buret, L, Rebillard, G, Brun, E, Angebault, C, Pequignot, M, Lenoir, M, Do-cruzeiro, M, Tournier, E, Cornille, K, Saleur, A, Gueguen, N, Reynier, P, Amati-Bonneau, P, Barakat, A, Blanchet, C, Chinnery, P, Yu-Wai-Man, P, Kaplan, J, Roux, A-F, Van Camp, G, Wissinger, B, Boespflug-Tanguy, O, Giraudet, F, Puel, J-L, Lenaers, G, Hamel, C, Delprat, B, Delettre, C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893315/
https://www.ncbi.nlm.nih.gov/pubmed/27275396
http://dx.doi.org/10.1038/cddiscovery.2016.17
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author Buret, L
Rebillard, G
Brun, E
Angebault, C
Pequignot, M
Lenoir, M
Do-cruzeiro, M
Tournier, E
Cornille, K
Saleur, A
Gueguen, N
Reynier, P
Amati-Bonneau, P
Barakat, A
Blanchet, C
Chinnery, P
Yu-Wai-Man, P
Kaplan, J
Roux, A-F
Van Camp, G
Wissinger, B
Boespflug-Tanguy, O
Giraudet, F
Puel, J-L
Lenaers, G
Hamel, C
Delprat, B
Delettre, C
author_facet Buret, L
Rebillard, G
Brun, E
Angebault, C
Pequignot, M
Lenoir, M
Do-cruzeiro, M
Tournier, E
Cornille, K
Saleur, A
Gueguen, N
Reynier, P
Amati-Bonneau, P
Barakat, A
Blanchet, C
Chinnery, P
Yu-Wai-Man, P
Kaplan, J
Roux, A-F
Van Camp, G
Wissinger, B
Boespflug-Tanguy, O
Giraudet, F
Puel, J-L
Lenaers, G
Hamel, C
Delprat, B
Delettre, C
author_sort Buret, L
collection PubMed
description In vertebrates, 14-3-3 proteins form a family of seven highly conserved isoforms with chaperone activity, which bind phosphorylated substrates mostly involved in regulatory and checkpoint pathways. 14-3-3 proteins are the most abundant protein in the brain and are abundantly found in the cerebrospinal fluid in neurodegenerative diseases, suggesting a critical role in neuron physiology and death. Here we show that 14-3-3eta-deficient mice displayed auditory impairment accompanied by cochlear hair cells' degeneration. We show that 14-3-3eta is highly expressed in the outer and inner hair cells, spiral ganglion neurons of cochlea and retinal ganglion cells. Screening of YWHAH, the gene encoding the 14-3-3eta isoform, in non-syndromic and syndromic deafness, revealed seven non-synonymous variants never reported before. Among them, two were predicted to be damaging in families with syndromic deafness. In vitro, variants of YWHAH induce mild mitochondrial fragmentation and severe susceptibility to apoptosis, in agreement with a reduced capacity of mutated 14-3-3eta to bind the pro-apoptotic Bad protein. This study demonstrates that YWHAH variants can have a substantial effect on 14-3-3eta function and that 14-3-3eta could be a critical factor in the survival of outer hair cells.
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spelling pubmed-48933152016-06-04 Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration Buret, L Rebillard, G Brun, E Angebault, C Pequignot, M Lenoir, M Do-cruzeiro, M Tournier, E Cornille, K Saleur, A Gueguen, N Reynier, P Amati-Bonneau, P Barakat, A Blanchet, C Chinnery, P Yu-Wai-Man, P Kaplan, J Roux, A-F Van Camp, G Wissinger, B Boespflug-Tanguy, O Giraudet, F Puel, J-L Lenaers, G Hamel, C Delprat, B Delettre, C Cell Death Discov Article In vertebrates, 14-3-3 proteins form a family of seven highly conserved isoforms with chaperone activity, which bind phosphorylated substrates mostly involved in regulatory and checkpoint pathways. 14-3-3 proteins are the most abundant protein in the brain and are abundantly found in the cerebrospinal fluid in neurodegenerative diseases, suggesting a critical role in neuron physiology and death. Here we show that 14-3-3eta-deficient mice displayed auditory impairment accompanied by cochlear hair cells' degeneration. We show that 14-3-3eta is highly expressed in the outer and inner hair cells, spiral ganglion neurons of cochlea and retinal ganglion cells. Screening of YWHAH, the gene encoding the 14-3-3eta isoform, in non-syndromic and syndromic deafness, revealed seven non-synonymous variants never reported before. Among them, two were predicted to be damaging in families with syndromic deafness. In vitro, variants of YWHAH induce mild mitochondrial fragmentation and severe susceptibility to apoptosis, in agreement with a reduced capacity of mutated 14-3-3eta to bind the pro-apoptotic Bad protein. This study demonstrates that YWHAH variants can have a substantial effect on 14-3-3eta function and that 14-3-3eta could be a critical factor in the survival of outer hair cells. Nature Publishing Group 2016-03-07 /pmc/articles/PMC4893315/ /pubmed/27275396 http://dx.doi.org/10.1038/cddiscovery.2016.17 Text en Copyright © 2016 Cell Death Differentiation Association http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Buret, L
Rebillard, G
Brun, E
Angebault, C
Pequignot, M
Lenoir, M
Do-cruzeiro, M
Tournier, E
Cornille, K
Saleur, A
Gueguen, N
Reynier, P
Amati-Bonneau, P
Barakat, A
Blanchet, C
Chinnery, P
Yu-Wai-Man, P
Kaplan, J
Roux, A-F
Van Camp, G
Wissinger, B
Boespflug-Tanguy, O
Giraudet, F
Puel, J-L
Lenaers, G
Hamel, C
Delprat, B
Delettre, C
Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration
title Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration
title_full Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration
title_fullStr Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration
title_full_unstemmed Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration
title_short Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration
title_sort loss of function of ywhah in mice induces deafness and cochlear outer hair cells' degeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893315/
https://www.ncbi.nlm.nih.gov/pubmed/27275396
http://dx.doi.org/10.1038/cddiscovery.2016.17
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