Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration
Identifieur interne : 001A43 ( Ncbi/Merge ); précédent : 001A42; suivant : 001A44Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration
Auteurs : L. Buret [France] ; G. Rebillard [France] ; E. Brun [France] ; C. Angebault [France] ; M. Pequignot [France] ; M. Lenoir [France] ; M. Do-Cruzeiro [France] ; E. Tournier [France] ; K. Cornille [France] ; A. Saleur [France] ; N. Gueguen [France] ; P. Reynier [France] ; P. Amati-Bonneau [France] ; A. Barakat [Maroc] ; C. Blanchet [France] ; P. Chinnery [Royaume-Uni] ; P. Yu-Wai-Man [Royaume-Uni] ; J. Kaplan [France] ; A-F Roux [France] ; G. Van Camp [Belgique] ; B. Wissinger [Allemagne] ; O. Boespflug-Tanguy [France] ; F. Giraudet [France] ; J-L Puel [France] ; G. Lenaers [France] ; C. Hamel [France] ; B. Delprat [France] ; C. Delettre [France]Source :
- Cell Death Discovery [ 2058-7716 ] ; 2016.
Abstract
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
Url:
DOI: 10.1038/cddiscovery.2016.17
PubMed: 27275396
PubMed Central: 4893315
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Buret</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Rebillard, G" sort="Rebillard, G" uniqKey="Rebillard G" first="G" last="Rebillard">G. Rebillard</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Brun, E" sort="Brun, E" uniqKey="Brun E" first="E" last="Brun">E. Brun</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Angebault, C" sort="Angebault, C" uniqKey="Angebault C" first="C" last="Angebault">C. Angebault</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pequignot, M" sort="Pequignot, M" uniqKey="Pequignot M" first="M" last="Pequignot">M. Pequignot</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lenoir, M" sort="Lenoir, M" uniqKey="Lenoir M" first="M" last="Lenoir">M. Lenoir</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Do Cruzeiro, M" sort="Do Cruzeiro, M" uniqKey="Do Cruzeiro M" first="M" last="Do-Cruzeiro">M. Do-Cruzeiro</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Homologuous Recombination, Cochin Institute, University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Tournier, E" sort="Tournier, E" uniqKey="Tournier E" first="E" last="Tournier">E. Tournier</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Homologuous Recombination, Cochin Institute, University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Cornille, K" sort="Cornille, K" uniqKey="Cornille K" first="K" last="Cornille">K. Cornille</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Saleur, A" sort="Saleur, A" uniqKey="Saleur A" first="A" last="Saleur">A. Saleur</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gueguen, N" sort="Gueguen, N" uniqKey="Gueguen N" first="N" last="Gueguen">N. Gueguen</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Ophthalmology, Angers University Hospital</institution>, Angers,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Reynier, P" sort="Reynier, P" uniqKey="Reynier P" first="P" last="Reynier">P. Reynier</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Ophthalmology, Angers University Hospital</institution>, Angers,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Amati Bonneau, P" sort="Amati Bonneau, P" uniqKey="Amati Bonneau P" first="P" last="Amati-Bonneau">P. Amati-Bonneau</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Ophthalmology, Angers University Hospital</institution>, Angers,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Barakat, A" sort="Barakat, A" uniqKey="Barakat A" first="A" last="Barakat">A. Barakat</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Laboratory of Human Genetic and Molecular Biology, Pasteur Institute</institution>, Casablanca,<country>Morocco</country></nlm:aff><country xml:lang="fr">Maroc</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Blanchet, C" sort="Blanchet, C" uniqKey="Blanchet C" first="C" last="Blanchet">C. Blanchet</name><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>CHRU Montpellier, Centre of Reference for Genetic Sensory Diseases, CHU, Gui de Chauliac Hospital</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Chinnery, P" sort="Chinnery, P" uniqKey="Chinnery P" first="P" last="Chinnery">P. Chinnery</name><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Mitochondrial Research Group, Institute of Ageing and Health, The Medical School, Newcastle University</institution>, Newcastle,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yu Wai Man, P" sort="Yu Wai Man, P" uniqKey="Yu Wai Man P" first="P" last="Yu-Wai-Man">P. Yu-Wai-Man</name><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Mitochondrial Research Group, Institute of Ageing and Health, The Medical School, Newcastle University</institution>, Newcastle,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kaplan, J" sort="Kaplan, J" uniqKey="Kaplan J" first="J" last="Kaplan">J. Kaplan</name><affiliation wicri:level="1"><nlm:aff id="aff8"><institution>Laboratory of Genetics in Ophthalmology, Inserm UMR1163, Institut Imagine, Université Paris Descartes Sorbonne Paris Cité, Hôpital Necker</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Roux, A F" sort="Roux, A F" uniqKey="Roux A" first="A-F" last="Roux">A-F Roux</name><affiliation wicri:level="1"><nlm:aff id="aff9"><institution>Laboratory of Molecular Genetic, CHU Arnaud de Villeneuve</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van Camp, G" sort="Van Camp, G" uniqKey="Van Camp G" first="G" last="Van Camp">G. Van Camp</name><affiliation wicri:level="1"><nlm:aff id="aff10"><institution>Center of Medical Genetics, Department of Biomedical Sciences, University of Antwerp</institution>, Antwerp,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wissinger, B" sort="Wissinger, B" uniqKey="Wissinger B" first="B" last="Wissinger">B. Wissinger</name><affiliation wicri:level="1"><nlm:aff id="aff11"><institution>Molecular Genetics Laboratory, Institute for Ophthalmic Research</institution>, Tuebingen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Boespflug Tanguy, O" sort="Boespflug Tanguy, O" uniqKey="Boespflug Tanguy O" first="O" last="Boespflug-Tanguy">O. Boespflug-Tanguy</name><affiliation wicri:level="1"><nlm:aff id="aff12"><institution>Neurobiology and Metabolic Diseases, Hospital Robert Debré</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Giraudet, F" sort="Giraudet, F" uniqKey="Giraudet F" first="F" last="Giraudet">F. Giraudet</name><affiliation wicri:level="1"><nlm:aff id="aff13"><institution>Laboratory of Neurosensorial Biophysic, UMR INSERM 1107, Faculty of Medicine – Auvergne University</institution>, Clermont Ferrand,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Puel, J L" sort="Puel, J L" uniqKey="Puel J" first="J-L" last="Puel">J-L Puel</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lenaers, G" sort="Lenaers, G" uniqKey="Lenaers G" first="G" last="Lenaers">G. Lenaers</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hamel, C" sort="Hamel, C" uniqKey="Hamel C" first="C" last="Hamel">C. Hamel</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>CHRU Montpellier, Centre of Reference for Genetic Sensory Diseases, CHU, Gui de Chauliac Hospital</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Delprat, B" sort="Delprat, B" uniqKey="Delprat B" first="B" last="Delprat">B. Delprat</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Delettre, C" sort="Delettre, C" uniqKey="Delettre C" first="C" last="Delettre">C. Delettre</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27275396</idno><idno type="pmc">4893315</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893315</idno><idno type="RBID">PMC:4893315</idno><idno type="doi">10.1038/cddiscovery.2016.17</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000182</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000182</idno><idno type="wicri:Area/Pmc/Curation">000181</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000181</idno><idno type="wicri:Area/Pmc/Checkpoint">000064</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000064</idno><idno type="wicri:Area/Ncbi/Merge">001A43</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Loss of function of <italic>Ywhah</italic> in mice induces deafness and cochlear outer hair cells' degeneration</title><author><name sortKey="Buret, L" sort="Buret, L" uniqKey="Buret L" first="L" last="Buret">L. Buret</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Rebillard, G" sort="Rebillard, G" uniqKey="Rebillard G" first="G" last="Rebillard">G. Rebillard</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Brun, E" sort="Brun, E" uniqKey="Brun E" first="E" last="Brun">E. Brun</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Angebault, C" sort="Angebault, C" uniqKey="Angebault C" first="C" last="Angebault">C. Angebault</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pequignot, M" sort="Pequignot, M" uniqKey="Pequignot M" first="M" last="Pequignot">M. Pequignot</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lenoir, M" sort="Lenoir, M" uniqKey="Lenoir M" first="M" last="Lenoir">M. Lenoir</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Do Cruzeiro, M" sort="Do Cruzeiro, M" uniqKey="Do Cruzeiro M" first="M" last="Do-Cruzeiro">M. Do-Cruzeiro</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Homologuous Recombination, Cochin Institute, University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Tournier, E" sort="Tournier, E" uniqKey="Tournier E" first="E" last="Tournier">E. Tournier</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Homologuous Recombination, Cochin Institute, University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Cornille, K" sort="Cornille, K" uniqKey="Cornille K" first="K" last="Cornille">K. Cornille</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Saleur, A" sort="Saleur, A" uniqKey="Saleur A" first="A" last="Saleur">A. Saleur</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gueguen, N" sort="Gueguen, N" uniqKey="Gueguen N" first="N" last="Gueguen">N. Gueguen</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Ophthalmology, Angers University Hospital</institution>, Angers,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Reynier, P" sort="Reynier, P" uniqKey="Reynier P" first="P" last="Reynier">P. Reynier</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Ophthalmology, Angers University Hospital</institution>, Angers,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Amati Bonneau, P" sort="Amati Bonneau, P" uniqKey="Amati Bonneau P" first="P" last="Amati-Bonneau">P. Amati-Bonneau</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Ophthalmology, Angers University Hospital</institution>, Angers,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Barakat, A" sort="Barakat, A" uniqKey="Barakat A" first="A" last="Barakat">A. Barakat</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Laboratory of Human Genetic and Molecular Biology, Pasteur Institute</institution>, Casablanca,<country>Morocco</country></nlm:aff><country xml:lang="fr">Maroc</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Blanchet, C" sort="Blanchet, C" uniqKey="Blanchet C" first="C" last="Blanchet">C. Blanchet</name><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>CHRU Montpellier, Centre of Reference for Genetic Sensory Diseases, CHU, Gui de Chauliac Hospital</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Chinnery, P" sort="Chinnery, P" uniqKey="Chinnery P" first="P" last="Chinnery">P. Chinnery</name><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Mitochondrial Research Group, Institute of Ageing and Health, The Medical School, Newcastle University</institution>, Newcastle,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yu Wai Man, P" sort="Yu Wai Man, P" uniqKey="Yu Wai Man P" first="P" last="Yu-Wai-Man">P. Yu-Wai-Man</name><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Mitochondrial Research Group, Institute of Ageing and Health, The Medical School, Newcastle University</institution>, Newcastle,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kaplan, J" sort="Kaplan, J" uniqKey="Kaplan J" first="J" last="Kaplan">J. Kaplan</name><affiliation wicri:level="1"><nlm:aff id="aff8"><institution>Laboratory of Genetics in Ophthalmology, Inserm UMR1163, Institut Imagine, Université Paris Descartes Sorbonne Paris Cité, Hôpital Necker</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Roux, A F" sort="Roux, A F" uniqKey="Roux A" first="A-F" last="Roux">A-F Roux</name><affiliation wicri:level="1"><nlm:aff id="aff9"><institution>Laboratory of Molecular Genetic, CHU Arnaud de Villeneuve</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van Camp, G" sort="Van Camp, G" uniqKey="Van Camp G" first="G" last="Van Camp">G. Van Camp</name><affiliation wicri:level="1"><nlm:aff id="aff10"><institution>Center of Medical Genetics, Department of Biomedical Sciences, University of Antwerp</institution>, Antwerp,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wissinger, B" sort="Wissinger, B" uniqKey="Wissinger B" first="B" last="Wissinger">B. Wissinger</name><affiliation wicri:level="1"><nlm:aff id="aff11"><institution>Molecular Genetics Laboratory, Institute for Ophthalmic Research</institution>, Tuebingen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Boespflug Tanguy, O" sort="Boespflug Tanguy, O" uniqKey="Boespflug Tanguy O" first="O" last="Boespflug-Tanguy">O. Boespflug-Tanguy</name><affiliation wicri:level="1"><nlm:aff id="aff12"><institution>Neurobiology and Metabolic Diseases, Hospital Robert Debré</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Giraudet, F" sort="Giraudet, F" uniqKey="Giraudet F" first="F" last="Giraudet">F. Giraudet</name><affiliation wicri:level="1"><nlm:aff id="aff13"><institution>Laboratory of Neurosensorial Biophysic, UMR INSERM 1107, Faculty of Medicine – Auvergne University</institution>, Clermont Ferrand,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Puel, J L" sort="Puel, J L" uniqKey="Puel J" first="J-L" last="Puel">J-L Puel</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lenaers, G" sort="Lenaers, G" uniqKey="Lenaers G" first="G" last="Lenaers">G. Lenaers</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hamel, C" sort="Hamel, C" uniqKey="Hamel C" first="C" last="Hamel">C. Hamel</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>CHRU Montpellier, Centre of Reference for Genetic Sensory Diseases, CHU, Gui de Chauliac Hospital</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Delprat, B" sort="Delprat, B" uniqKey="Delprat B" first="B" last="Delprat">B. Delprat</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Delettre, C" sort="Delettre, C" uniqKey="Delettre C" first="C" last="Delettre">C. Delettre</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Cell Death Discovery</title><idno type="eISSN">2058-7716</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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 <italic>YWHAH</italic>, 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. <italic>In vitro</italic>, variants of <italic>YWHAH</italic> 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 <italic>YWHAH</italic> 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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Death Discov</journal-id><journal-id journal-id-type="iso-abbrev">Cell Death Discov</journal-id><journal-title-group><journal-title>Cell Death Discovery</journal-title></journal-title-group><issn pub-type="epub">2058-7716</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27275396</article-id><article-id pub-id-type="pmc">4893315</article-id><article-id pub-id-type="pii">cddiscovery201617</article-id><article-id pub-id-type="doi">10.1038/cddiscovery.2016.17</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Loss of function of <italic>Ywhah</italic> in mice induces deafness and cochlear outer hair cells' degeneration</article-title><alt-title alt-title-type="running"><italic>Ywhah</italic> loss of function induces deafness</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Buret</surname><given-names>L</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Rebillard</surname><given-names>G</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Brun</surname><given-names>E</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Angebault</surname><given-names>C</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Pequignot</surname><given-names>M</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Lenoir</surname><given-names>M</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Do-cruzeiro</surname><given-names>M</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Tournier</surname><given-names>E</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Cornille</surname><given-names>K</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Saleur</surname><given-names>A</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Gueguen</surname><given-names>N</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Reynier</surname><given-names>P</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Amati-Bonneau</surname><given-names>P</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Barakat</surname><given-names>A</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Blanchet</surname><given-names>C</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Chinnery</surname><given-names>P</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Yu-Wai-Man</surname><given-names>P</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Kaplan</surname><given-names>J</given-names></name><xref ref-type="aff" rid="aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Roux</surname><given-names>A-F</given-names></name><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Van Camp</surname><given-names>G</given-names></name><xref ref-type="aff" rid="aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Wissinger</surname><given-names>B</given-names></name><xref ref-type="aff" rid="aff11">11</xref></contrib><contrib contrib-type="author"><name><surname>Boespflug-Tanguy</surname><given-names>O</given-names></name><xref ref-type="aff" rid="aff12">12</xref></contrib><contrib contrib-type="author"><name><surname>Giraudet</surname><given-names>F</given-names></name><xref ref-type="aff" rid="aff13">13</xref></contrib><contrib contrib-type="author"><name><surname>Puel</surname><given-names>J-L</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Lenaers</surname><given-names>G</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hamel</surname><given-names>C</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Delprat</surname><given-names>B</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Delettre</surname><given-names>C</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><aff id="aff1"><label>1</label><institution>INSERM U1051, Institute of Neurosciences of Montpellier</institution>, Montpellier,<country>France</country></aff><aff id="aff2"><label>2</label><institution>Department of Biology and Health Sciences, University of Montpellier</institution>, Montpellier,<country>France</country></aff><aff id="aff3"><label>3</label><institution>Homologuous Recombination, Cochin Institute, University Paris Descartes</institution>, Paris,<country>France</country></aff><aff id="aff4"><label>4</label><institution>Department of Ophthalmology, Angers University Hospital</institution>, Angers,<country>France</country></aff><aff id="aff5"><label>5</label><institution>Laboratory of Human Genetic and Molecular Biology, Pasteur Institute</institution>, Casablanca,<country>Morocco</country></aff><aff id="aff6"><label>6</label><institution>CHRU Montpellier, Centre of Reference for Genetic Sensory Diseases, CHU, Gui de Chauliac Hospital</institution>, Montpellier,<country>France</country></aff><aff id="aff7"><label>7</label><institution>Mitochondrial Research Group, Institute of Ageing and Health, The Medical School, Newcastle University</institution>, Newcastle,<country>UK</country></aff><aff id="aff8"><label>8</label><institution>Laboratory of Genetics in Ophthalmology, Inserm UMR1163, Institut Imagine, Université Paris Descartes Sorbonne Paris Cité, Hôpital Necker</institution>, Paris,<country>France</country></aff><aff id="aff9"><label>9</label><institution>Laboratory of Molecular Genetic, CHU Arnaud de Villeneuve</institution>, Montpellier,<country>France</country></aff><aff id="aff10"><label>10</label><institution>Center of Medical Genetics, Department of Biomedical Sciences, University of Antwerp</institution>, Antwerp,<country>Belgium</country></aff><aff id="aff11"><label>11</label><institution>Molecular Genetics Laboratory, Institute for Ophthalmic Research</institution>, Tuebingen,<country>Germany</country></aff><aff id="aff12"><label>12</label><institution>Neurobiology and Metabolic Diseases, Hospital Robert Debré</institution>, Paris,<country>France</country></aff><aff id="aff13"><label>13</label><institution>Laboratory of Neurosensorial Biophysic, UMR INSERM 1107, Faculty of Medicine – Auvergne University</institution>, Clermont Ferrand,<country>France</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label>(<email>cecile.delettre@inserm.fr</email>)</corresp></author-notes><pub-date pub-type="epub"><day>07</day><month>03</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>2</volume><fpage>16017</fpage><lpage></lpage><history><date date-type="received"><day>12</day><month>10</month><year>2015</year></date><date date-type="rev-recd"><day>25</day><month>01</month><year>2016</year></date><date date-type="accepted"><day>26</day><month>01</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016 Cell Death Differentiation Association</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Cell Death Differentiation Association</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>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 <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>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 <italic>YWHAH</italic>, 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. <italic>In vitro</italic>, variants of <italic>YWHAH</italic> 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 <italic>YWHAH</italic> 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.</p></abstract></article-meta></front><floats-group><fig id="fig1"><label>Figure 1</label><caption><p>Invalidation of Ywhah induces a mild deafness but does not affect the functioning of the stria vascularis. (<bold>a</bold>) Audiograms established in 14-3-3eta<sup>WT/WT</sup> (<italic>n</italic>=18), 14-3-3eta<sup>GT/WT</sup> (<italic>n</italic>=16) and 14-3-3eta<sup>GT/GT</sup> (<italic>n</italic>=20) by measuring the brainstem evoked potential thresholds at 10 frequencies ranging from 2 to 32 kHz. Data show a mild (10–20 decibels (dB)) but very significant (<italic>P</italic><0.01 for all tested frequencies) threshold elevation in 14-3-3eta<sup>GT/WT</sup> (blue triangles) and 14-3-3eta<sup>GT/GT</sup> (red squares) mice as compared with 14-3-3eta<sup>WT/WT</sup> (green circles) at 2, 4 and 6 months. (<bold>b</bold>) This panel displays cubic DPOAE (2<italic>f</italic><sub>1</sub>−<italic>f</italic><sub>2</sub>) audiograms represented as a function of <italic>f</italic><sub>2</sub>. The magnitude of the distortion product is slightly reduced in 14-3-3eta<sup>GT/WT</sup> (blue triangles; <italic>n</italic>=14) and 14-3-3eta<sup>GT/GT</sup> (red squares; <italic>n</italic>= 6) as compared with 14-3-3eta<sup>WT/WT</sup> mice (green circles; <italic>n</italic>=14). This reduction is significant between 6 and 20 kHz. The gray line represents the noise floor. (<bold>c</bold>) Endocochlear potentials were recorded in 14-3-3eta<sup>WT/WT</sup> (green bar; <italic>n</italic>=5), 14-3-3eta<sup>GT/WT</sup> (blue bar; <italic>n</italic>=5) and 14-3-3eta<sup>GT/GT</sup> mice (red bar; <italic>n</italic>=5). No significant difference was seen between the three genotypes. Data are mean±S.E.M.</p></caption><graphic xlink:href="cddiscovery201617-f1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Degeneration of cochlear cells in 14-3-3eta mutant mice. Scanning electron microscopy of the organ of Corti at the apical turn (A; <bold>a</bold>–<bold>c</bold>), the middle turn (M; <bold>d</bold>–<bold>f</bold>) , the upper basal turn (B2; <bold>g</bold>–<bold>i</bold>) and the lower basal turn (B1; <bold>j</bold>–<bold>l</bold>) obtained from 6-month-old 14-3-3eta<sup>WT/WT</sup> (<bold>a</bold>, <bold>d</bold>, <bold>g</bold> and <bold>j</bold>), 14-3-3eta<sup>GT/WT</sup> (<bold>b</bold>, <bold>e</bold>, <bold>h</bold> and <bold>k</bold>) and 14-3-3eta<sup>GT/GT</sup> (<bold>c</bold>, <bold>f</bold>, <bold>i</bold> and <bold>l</bold>) mice. Both IHCs and OHCs are regularly aligned in the apical and middle turn of all genotype. In the basal turn (B1, B2) OHCs loss is observed in 14-3-3eta<sup>GT/WT</sup> and 14-3-3eta<sup>GT/GT</sup>. Scale bars: 5 <italic>μ</italic>m.</p></caption><graphic xlink:href="cddiscovery201617-f2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>14-3-3eta expression in cochlea. Microdissected adult (P30) mice cochlea were stained with Hoechst and immuno-labeled with an anti-14-3-3eta antibody (in green) and antiparvalbumin antibody (in red) to identify hair cells and spiral ganglion neurons. (<bold>a</bold>) Strong expression of 14-3-3eta was localized in inner (IHC) and OHCs, pillar cells (P) and spiral ganglion (SG). (<bold>b</bold>) Higher magnification image of organ of Corti showing staining of hair cells and pillar cells. (<bold>c</bold>) Higher magnification image of spiral ganglion neurons. (<bold>d</bold>) Control section of cochlea. (<bold>e</bold>) Control section of the organ of Corti. (<bold>f</bold>) Control section of spiral ganglion neurons showing no staining. Scale bar represents 100 <italic>μ</italic>m.</p></caption><graphic xlink:href="cddiscovery201617-f3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Expression of 14-3-3 transcripts in mouse retina and cochlea. Relative mRNA expression of 14-3-3 transcripts in mouse cochlea and retina were quantified by qPCR. Data are mean±S.E.M.</p></caption><graphic xlink:href="cddiscovery201617-f4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Detection of apoptosis by TUNEL assay in control and mutant cochlea. (<bold>a</bold>, <bold>e</bold>, <bold>i</bold>) Wild-type and mutant organ of Corti immunostained for Myosine VIIa (green) to detect hair cells. (<bold>b</bold>, <bold>f</bold>, <bold>j</bold>) DAPI (blue) and (<bold>c</bold>, <bold>g</bold>, <bold>k</bold>) TUNEL (red) staining observed in the organ of Corti in basal turn for 14-3-3eta<sup>WT/WT</sup>, 14-3-3eta<sup>GT/WT</sup> and 14-3-3eta<sup>GT/GT</sup>. (<bold>c</bold>) No TUNEL-positive cells were detected in the control cochlea. (<bold>g</bold>, <bold>k</bold>) Positive TUNEL staining was seen in both 14-3-3eta<sup>GT/WT</sup> and 14-3-3eta<sup>GT/GT</sup>. (<bold>d</bold>, <bold>h</bold>, <bold>l</bold>) Merge images with Myosine VIIa (green), DAPI (blue) and TUNEL (red). Scale bar=20 <italic>μ</italic>m.</p></caption><graphic xlink:href="cddiscovery201617-f5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>Identification of damaging variants in <italic>YWHAH</italic> gene. (<bold>a</bold>) Intron–exon structure of the <italic>YWHAH</italic> gene and position of variants in exon 2 (top). From top to bottom, schematic representation of the 14-3-3eta protein, position of variants and consequence of the deletion in protein translation (the gray box represents the frameshift, dotted lines represent truncative part of the protein). (<bold>b</bold>) Amino-acid alignment of the C-terminal domain of different 14-3-3 isoforms (top) and of 14-3-3eta from different species (bottom) showing the conserved aspartate at position 236. Conserved, semi-conserved and non-conserved substitutions are framed in black, gray and white boxes, respectively.</p></caption><graphic xlink:href="cddiscovery201617-f6"></graphic></fig><fig id="fig7"><label>Figure 7</label><caption><p>Impact of <italic>YWHAH</italic> variants in human fibroblasts. Fibroblasts from patients (family 1: the father ∆1 and his son ∆2, family 2: D236N) were compared in all experiments with three control fibroblast cultures obtained from healthy patients. (<bold>a</bold>) Susceptibility to apoptosis was assessed by counting apoptotic nuclei after a 3-h staurosporine treatment (1 <italic>μ</italic>M; <italic>n</italic>=3). (<bold>b</bold>) Mitochondrial network structure was assessed on exponential growing cultures after Mitotracker staining. Filamentous, fragmented and punctuated phenotypes were counted on 200 cells in 3 independent experiments. Data are mean±S.E.M. (<bold>c</bold>) HeLa cells were transiently transfected with pIRES-EGFP vectors expressing 14-3-3eta, 14-3-3eta ∆189 and 14-3-3eta D236N. Western blotting of total cell lysate showing the expression of the different proteins (arrows). Actin was used as a loading control. (<bold>d</bold>) In a parallel experiment, HeLa cells were treated with 1 <italic>μ</italic>M staurosporine for 3 h before the quantification of apoptotic cells. Apoptosis was assessed by immunofluorescent detection (top) of the active form of caspase<italic>-</italic>3 (red fluorescence) in transfected cells (green fluorescence). All cells were stained with the nuclear marker Hoechst. Scale bar represents 20 <italic>μ</italic>m. Quantification of apoptosis in transfected cells (bottom), each point representing the average of triplicate±S.E.M.</p></caption><graphic xlink:href="cddiscovery201617-f7"></graphic></fig><fig id="fig8"><label>Figure 8</label><caption><p>Impact of <italic>YWHAH</italic> variants on Bad interaction. After transfection of empty vector pcDNA-V5, 14-3-3eta-V5, 14-3-3eta∆189-V5 and 14-3-3D236N-V5 in HeLa cells, the production of the protein was verified by western blotting (Input, middle panel), and immunoprecipitation studies were performed with the Bad antibody. The presence of 14-3-3eta in the Bad complex was shown by immunoblot with the rabbit anti-V5 antibody (IP Bad, top panel). The antibody used for the immunoblot analysis is denoted at the right side. Cell lysates were immunoblotted with the Bad antibody as a control (Input, bottom panel).</p></caption><graphic xlink:href="cddiscovery201617-f8"></graphic></fig><table-wrap id="tbl1"><label>Table 1</label><caption><title><italic>YWHAH</italic> variants detected in non-syndromic and syndromic deafness</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><italic>Family</italic></th><th align="center" valign="top" charoff="50"><italic>Nucleotide change</italic></th><th align="center" valign="top" charoff="50"><italic>Amino-acid change</italic></th><th align="center" valign="top" charoff="50"><italic>Status</italic></th><th align="center" valign="top" charoff="50"><italic>Localization</italic></th><th align="center" valign="top" charoff="50"><italic>Phenotype</italic></th><th align="center" valign="top" charoff="50"><italic>Polyphen2 (score)</italic></th><th align="center" valign="top" charoff="50"><italic>SIFT (score)</italic></th><th align="center" valign="top" charoff="50"><italic>Provean (score)</italic></th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50">c.172del25</td><td align="left" valign="top" charoff="50">p.Ser58Leufs*43</td><td align="left" valign="top" charoff="50">Heterozygous</td><td align="left" valign="top" charoff="50">Exon 2</td><td align="left" valign="top" charoff="50">Deafness+OA</td><td align="left" valign="top" charoff="50">NA</td><td align="left" valign="top" charoff="50">NA</td><td align="left" valign="top" charoff="50">Deleterious (−139.3)</td></tr><tr><td align="left" valign="top" charoff="50">2</td><td align="left" valign="top" charoff="50">c.706G>A</td><td align="left" valign="top" charoff="50">p.Asp236Asn</td><td align="left" valign="top" charoff="50">Heterozygous</td><td align="left" valign="top" charoff="50">Exon 2</td><td align="left" valign="top" charoff="50">Deafness+OA</td><td align="left" valign="top" charoff="50">Probably damaging (0.998)</td><td align="left" valign="top" charoff="50">Affect protein function(0.0)</td><td align="left" valign="top" charoff="50">Deleterious (0.998)</td></tr><tr><td align="left" valign="top" charoff="50">3</td><td align="left" valign="top" charoff="50">c.722A>C</td><td align="left" valign="top" charoff="50">p.Glu241Ala</td><td align="left" valign="top" charoff="50">Heterozygous</td><td align="left" valign="top" charoff="50">Exon 2</td><td align="left" valign="top" charoff="50">Familial deafness</td><td align="left" valign="top" charoff="50">Possibly damaging (0.698)</td><td align="left" valign="top" charoff="50">Affect protein function (0.01)</td><td align="left" valign="top" charoff="50">Neutral</td></tr><tr><td align="left" valign="top" charoff="50">4</td><td align="left" valign="top" charoff="50">IVS1+67 C>T</td><td align="left" valign="top" charoff="50">No change</td><td align="left" valign="top" charoff="50">Heterozygous</td><td align="left" valign="top" charoff="50">Intron 1</td><td align="left" valign="top" charoff="50">Familial deafness</td><td align="left" valign="top" charoff="50">NA</td><td align="left" valign="top" charoff="50">NA</td><td align="left" valign="top" charoff="50">NA</td></tr><tr><td align="left" valign="top" charoff="50">5</td><td align="left" valign="top" charoff="50">c.104A>G</td><td align="left" valign="top" charoff="50">p.Glu35Gly</td><td align="left" valign="top" charoff="50">Heterozygous</td><td align="left" valign="top" charoff="50">Exon 2</td><td align="left" valign="top" charoff="50">Familial deafness</td><td align="left" valign="top" charoff="50">Possibly damaging (0.552)</td><td align="left" valign="top" charoff="50">Affect protein function (0.0)</td><td align="left" valign="top" charoff="50">Neutral</td></tr><tr><td align="left" valign="top" charoff="50">6</td><td align="left" valign="top" charoff="50">c.187A>G</td><td align="left" valign="top" charoff="50">p.Ile63Val</td><td align="left" valign="top" charoff="50">Heterozygous</td><td align="left" valign="top" charoff="50">Exon 2</td><td align="left" valign="top" charoff="50">Sporadic deafness</td><td align="left" valign="top" charoff="50">Benign</td><td align="left" valign="top" charoff="50">Affect protein function (0.05)</td><td align="left" valign="top" charoff="50">Neutral</td></tr><tr><td align="left" valign="top" charoff="50">7</td><td align="left" valign="top" charoff="50">c.295A>G</td><td align="left" valign="top" charoff="50">p.Asn98Ser</td><td align="left" valign="top" charoff="50">Heterozygous</td><td align="left" valign="top" charoff="50">Exon 2</td><td align="left" valign="top" charoff="50">Sporadic deafness</td><td align="left" valign="top" charoff="50">Benign</td><td align="left" valign="top" charoff="50">Affect protein function (0.02)</td><td align="left" valign="top" charoff="50">Neutral</td></tr><tr><td align="left" valign="top" charoff="50">8</td><td align="left" valign="top" charoff="50">c.338A>G</td><td align="left" valign="top" charoff="50">p.Asn113Ser</td><td align="left" valign="top" charoff="50">Heterozygous</td><td align="left" valign="top" charoff="50">Exon 2</td><td align="left" valign="top" charoff="50">Sporadic deafness</td><td align="left" valign="top" charoff="50">Benign</td><td align="left" valign="top" charoff="50">Tolerated (1.00)</td><td align="left" valign="top" charoff="50">Neutral</td></tr></tbody></table><table-wrap-foot><fn id="t1-tfoot1"><p>Abbreviation: NA, not applicable.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list><country><li>Allemagne</li><li>Belgique</li><li>France</li><li>Maroc</li><li>Royaume-Uni</li></country></list><tree><country name="France"><noRegion><name sortKey="Buret, L" sort="Buret, L" uniqKey="Buret L" first="L" last="Buret">L. Buret</name></noRegion><name sortKey="Amati Bonneau, P" sort="Amati Bonneau, P" uniqKey="Amati Bonneau P" first="P" last="Amati-Bonneau">P. Amati-Bonneau</name><name sortKey="Angebault, C" sort="Angebault, C" uniqKey="Angebault C" first="C" last="Angebault">C. Angebault</name><name sortKey="Angebault, C" sort="Angebault, C" uniqKey="Angebault C" first="C" last="Angebault">C. Angebault</name><name sortKey="Blanchet, C" sort="Blanchet, C" uniqKey="Blanchet C" first="C" last="Blanchet">C. Blanchet</name><name sortKey="Boespflug Tanguy, O" sort="Boespflug Tanguy, O" uniqKey="Boespflug Tanguy O" first="O" last="Boespflug-Tanguy">O. Boespflug-Tanguy</name><name sortKey="Brun, E" sort="Brun, E" uniqKey="Brun E" first="E" last="Brun">E. Brun</name><name sortKey="Brun, E" sort="Brun, E" uniqKey="Brun E" first="E" last="Brun">E. Brun</name><name sortKey="Buret, L" sort="Buret, L" uniqKey="Buret L" first="L" last="Buret">L. Buret</name><name sortKey="Cornille, K" sort="Cornille, K" uniqKey="Cornille K" first="K" last="Cornille">K. Cornille</name><name sortKey="Cornille, K" sort="Cornille, K" uniqKey="Cornille K" first="K" last="Cornille">K. Cornille</name><name sortKey="Delettre, C" sort="Delettre, C" uniqKey="Delettre C" first="C" last="Delettre">C. Delettre</name><name sortKey="Delettre, C" sort="Delettre, C" uniqKey="Delettre C" first="C" last="Delettre">C. Delettre</name><name sortKey="Delprat, B" sort="Delprat, B" uniqKey="Delprat B" first="B" last="Delprat">B. Delprat</name><name sortKey="Delprat, B" sort="Delprat, B" uniqKey="Delprat B" first="B" last="Delprat">B. Delprat</name><name sortKey="Do Cruzeiro, M" sort="Do Cruzeiro, M" uniqKey="Do Cruzeiro M" first="M" last="Do-Cruzeiro">M. Do-Cruzeiro</name><name sortKey="Giraudet, F" sort="Giraudet, F" uniqKey="Giraudet F" first="F" last="Giraudet">F. Giraudet</name><name sortKey="Gueguen, N" sort="Gueguen, N" uniqKey="Gueguen N" first="N" last="Gueguen">N. Gueguen</name><name sortKey="Hamel, C" sort="Hamel, C" uniqKey="Hamel C" first="C" last="Hamel">C. Hamel</name><name sortKey="Hamel, C" sort="Hamel, C" uniqKey="Hamel C" first="C" last="Hamel">C. Hamel</name><name sortKey="Hamel, C" sort="Hamel, C" uniqKey="Hamel C" first="C" last="Hamel">C. Hamel</name><name sortKey="Kaplan, J" sort="Kaplan, J" uniqKey="Kaplan J" first="J" last="Kaplan">J. Kaplan</name><name sortKey="Lenaers, G" sort="Lenaers, G" uniqKey="Lenaers G" first="G" last="Lenaers">G. Lenaers</name><name sortKey="Lenaers, G" sort="Lenaers, G" uniqKey="Lenaers G" first="G" last="Lenaers">G. Lenaers</name><name sortKey="Lenoir, M" sort="Lenoir, M" uniqKey="Lenoir M" first="M" last="Lenoir">M. Lenoir</name><name sortKey="Lenoir, M" sort="Lenoir, M" uniqKey="Lenoir M" first="M" last="Lenoir">M. Lenoir</name><name sortKey="Pequignot, M" sort="Pequignot, M" uniqKey="Pequignot M" first="M" last="Pequignot">M. Pequignot</name><name sortKey="Pequignot, M" sort="Pequignot, M" uniqKey="Pequignot M" first="M" last="Pequignot">M. Pequignot</name><name sortKey="Puel, J L" sort="Puel, J L" uniqKey="Puel J" first="J-L" last="Puel">J-L Puel</name><name sortKey="Puel, J L" sort="Puel, J L" uniqKey="Puel J" first="J-L" last="Puel">J-L Puel</name><name sortKey="Rebillard, G" sort="Rebillard, G" uniqKey="Rebillard G" first="G" last="Rebillard">G. Rebillard</name><name sortKey="Rebillard, G" sort="Rebillard, G" uniqKey="Rebillard G" first="G" last="Rebillard">G. Rebillard</name><name sortKey="Reynier, P" sort="Reynier, P" uniqKey="Reynier P" first="P" last="Reynier">P. Reynier</name><name sortKey="Roux, A F" sort="Roux, A F" uniqKey="Roux A" first="A-F" last="Roux">A-F Roux</name><name sortKey="Saleur, A" sort="Saleur, A" uniqKey="Saleur A" first="A" last="Saleur">A. Saleur</name><name sortKey="Saleur, A" sort="Saleur, A" uniqKey="Saleur A" first="A" last="Saleur">A. Saleur</name><name sortKey="Tournier, E" sort="Tournier, E" uniqKey="Tournier E" first="E" last="Tournier">E. Tournier</name></country><country name="Maroc"><noRegion><name sortKey="Barakat, A" sort="Barakat, A" uniqKey="Barakat A" first="A" last="Barakat">A. Barakat</name></noRegion></country><country name="Royaume-Uni"><noRegion><name sortKey="Chinnery, P" sort="Chinnery, P" uniqKey="Chinnery P" first="P" last="Chinnery">P. Chinnery</name></noRegion><name sortKey="Yu Wai Man, P" sort="Yu Wai Man, P" uniqKey="Yu Wai Man P" first="P" last="Yu-Wai-Man">P. Yu-Wai-Man</name></country><country name="Belgique"><noRegion><name sortKey="Van Camp, G" sort="Van Camp, G" uniqKey="Van Camp G" first="G" last="Van Camp">G. Van Camp</name></noRegion></country><country name="Allemagne"><noRegion><name sortKey="Wissinger, B" sort="Wissinger, B" uniqKey="Wissinger B" first="B" last="Wissinger">B. 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