Mutations in the Pejvakin (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 co-localizes with the rootlet component TRIOBP at the base of stereocilia in injectoporated hair cells, a pattern that is disrupted by deafness-associated PJVK mutations. Hair cells of pejvakin-deficient mice develop normal rootlets, but hair bundle morphology and mechanotransduction are affected prior to the onset of hearing. Some mechanotransducing shorter row stereocilia are missing, while the remaining ones exhibit over-extended tips and a greater variability in height and width. Unlike previous studies of Pjvk alleles with neuronal dysfunction, our findings reveal a cell-autonomous role of pejvakin in maintaining stereocilia architecture that is critical for hair cell function.
Two missense mutations in the Pejvakin (PJVK or DFNB59) gene were first identified in patients with audiological hallmarks of auditory neuropathy spectrum disorder (ANSD) while all other PJVK alleles 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.
The authors declare no competing financial interests.
We thank Nadiya Chuchvara, Clare Cutri-French and other members of the Schwander laboratory for helpful discussions and Ulrich Mueller for kindly supplying the Otof-Cre mouse strain. We thank Wei Xiong for advice on injectoporation techniques, Lisa Goodrich for Ngn1-CreERT2 mice and Thomas Friedman and Inna Belyantseva for supplying the TRIOBP-5 and TRIOBP-4/5 antisera. We thank Chantal Cazvieille and Alicia Caballero (Technological plateau COMET of Montpellier) for help with electron microscopy and preparation of TEM sections. This work was funded by NIH grant DC013331 (M.S), Rutgers the State University of New Jersey (M.S.), Busch Biomedical grant (M.S.), a fellowship from the Capita Foundation for Hearing Research (M.S.), NIH grant DC003896 to Anthony Ricci, and NIH grant DC013299 (A.W.P.). The generation of the floxed Pjvk allele was carried out with funding from the NIDCD to Ulrich Mueller (DC014713, DC007704). This work was also supported by the Inserm Grant (U1051-Dot 02) and by the Fondation “Gueules Cassées (09-2014)”. Piotr Kazmierczak is a recipient of a Montpellier University postdoctoral fellowship.