Loss of function ofYwhahin 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 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 ofYWHAH, 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 ofYWHAHinduce 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 thatYWHAHvariants 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.
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
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L
Buret
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
G
G
Rebillard
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
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Brun
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
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Angebault
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
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Pequignot
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
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Lenoir
Homologuous Recombination, Cochin Institute, University Paris Descartes, Paris, France.
M
M
Do-Cruzeiro
Homologuous Recombination, Cochin Institute, University Paris Descartes, Paris, France.
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Tournier
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
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Cornille
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
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Saleur
Department of Ophthalmology, Angers University Hospital, Angers, France.
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N
Gueguen
Department of Ophthalmology, Angers University Hospital, Angers, France.
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Reynier
Department of Ophthalmology, Angers University Hospital, Angers, France.
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P
Amati-Bonneau
Laboratory of Human Genetic and Molecular Biology, Pasteur Institute, Casablanca, Morocco.
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A
Barakat
CHRU Montpellier, Centre of Reference for Genetic Sensory Diseases, CHU, Gui de Chauliac Hospital, Montpellier, France.
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Blanchet
Mitochondrial Research Group, Institute of Ageing and Health, The Medical School, Newcastle University, Newcastle, UK.
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P
Chinnery
Mitochondrial Research Group, Institute of Ageing and Health, The Medical School, Newcastle University, Newcastle, UK.
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P
Yu-Wai-Man
Laboratory of Genetics in Ophthalmology, Inserm UMR1163, Institut Imagine, Université Paris Descartes Sorbonne Paris Cité, Hôpital Necker, Paris, France.
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Kaplan
Laboratory of Molecular Genetic, CHU Arnaud de Villeneuve, Montpellier, France.
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Roux
Center of Medical Genetics, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
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Van Camp
Molecular Genetics Laboratory, Institute for Ophthalmic Research, Tuebingen, Germany.
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Wissinger
Neurobiology and Metabolic Diseases, Hospital Robert Debré, Paris, France.
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Boespflug-Tanguy
Laboratory of Neurosensorial Biophysic, UMR INSERM 1107, Faculty of Medicine - Auvergne University, Clermont Ferrand, France.
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Giraudet
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
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Puel
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
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Lenaers
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France; CHRU Montpellier, Centre of Reference for Genetic Sensory Diseases, CHU, Gui de Chauliac Hospital, Montpellier, France.
C
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Hamel
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
B
B
Delprat
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France; Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
C
C
Delettre