title: Pejvakin, a Candidate Stereociliary Rootlet Protein, Regulates Hair Cell Function in a Cell-Autonomous Manner.
abstract: Mutations in thePejvakin(PJVK) gene are thought to cause auditory neuropathy and hearing loss of cochlear origin by affecting noise-induced peroxisome proliferation in auditory hair cells and neurons. Here we demonstrate that loss of pejvakin in hair cells, but not in neurons, causes profound hearing loss and outer hair cell degeneration in mice. Pejvakin binds to and colocalizes with the rootlet component TRIOBP at the base of stereocilia in injectoporated hair cells, a pattern that is disrupted by deafness-associatedPJVKmutations. Hair cells of pejvakin-deficient mice develop normal rootlets, but hair bundle morphology and mechanotransduction are affected before the onset of hearing. Some mechanotransducing shorter row stereocilia are missing, whereas the remaining ones exhibit overextended tips and a greater variability in height and width. Unlike previous studies ofPjvkalleles with neuronal dysfunction, our findings reveal a cell-autonomous role of pejvakin in maintaining stereocilia architecture that is critical for hair cell function.SIGNIFICANCE STATEMENTTwo missense mutations in thePejvakin(PJVKorDFNB59) gene were first identified in patients with audiological hallmarks of auditory neuropathy spectrum disorder, whereas all otherPJVKalleles cause hearing loss of cochlear origin. These findings suggest that complex pathogenetic mechanisms underlie human deafness DFNB59. In contrast to recent studies, we demonstrate that pejvakin in auditory neurons is not essential for normal hearing in mice. Moreover, pejvakin localizes to stereociliary rootlets in hair cells and is required for stereocilia maintenance and mechanosensory function of the hair bundle. Delineating the site of the lesion and the mechanisms underlying DFNB59 will allow clinicians to predict the efficacy of different therapeutic approaches, such as determining compatibility for cochlear implants.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers the State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Marcin
authors.identifier: 0000-0002-4912-785X
authors.initials: M
authors.lastname: Kazmierczak
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, 34091, Montpellier cedex 5, France.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kazmierczak
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Stanford University, Stanford, California 94305.|Department of Physiology and Biophysics, University of Colorado School of Medicine, Aurora, Colorado 80045, and.
authors.forename: Anthony W
authors.identifier: 0000-0002-2208-6779
authors.initials: AW
authors.lastname: Peng
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers the State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Suzan L
authors.initials: SL
authors.lastname: Harris
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers the State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Prahar
authors.initials: P
authors.lastname: Shah
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, 34091, Montpellier cedex 5, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Puel
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, 34091, Montpellier cedex 5, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lenoir
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045.
authors.forename: Santos J
authors.identifier: 0000-0002-4478-5634
authors.initials: SJ
authors.lastname: Franco
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers the State University of New Jersey, Piscataway, New Jersey 08854, schwander@biology.rutgers.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwander
mesh_terms: D000818:Animals; D002460:Cell Line; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000473:pathology*; D006309:Hearing; D006319:Hearing Loss, Sensorineural / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D059547:Stereocilia / Q000378:metabolism / Q000473:pathology; D000094524:Gasdermins
chemical_list: D008840:Microfilament Proteins; D011506:Proteins; C550098:TRIOBP protein, mouse; C000605138:pejvakin protein, mouse; D000094524:Gasdermins
keywords: DFNB59; auditory neuropathy spectrum disorder; hair cell; hearing loss; inner ear; pejvakin