TY - JOUR T1 - Pejvakin, a Candidate Stereociliary Rootlet Protein, Regulates Hair Cell Function in a Cell-Autonomous Manner. JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.2711-16.2017 SP - 2711-16 AU - Marcin Kazmierczak AU - Piotr Kazmierczak AU - Anthony W. Peng AU - Suzan L. Harris AU - Prahar Shah AU - Jean-Luc Puel AU - Marc Lenoir AU - Santos J. Franco AU - Martin Schwander Y1 - 2017/02/16 UR - http://www.jneurosci.org/content/early/2017/02/16/JNEUROSCI.2711-16.2017.abstract N2 - 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.SIGNIFICANCE STATEMENTTwo 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. ER -