title: Conditional deletion of pejvakin in adult outer hair cells causes progressive hearing loss in mice.
abstract: Mutations in the Pejvakin (Pjvk) gene cause autosomal recessive hearing loss DFNB59 with audiological features of auditory neuropathy spectrum disorder (ANSD) or cochlear dysfunction. The precise mechanisms underlying the variable clinical phenotypes of DFNB59 remain unclear. Here, we demonstrate that mice with conditional ablation of the Pjvk gene in all sensory hair cells or only in outer hair cells (OHCs) show similar auditory phenotypes with early-onset profound hearing loss. By contrast, loss of Pjvk in adult OHCs causes a slowly progressive hearing loss associated with OHC degeneration and delayed loss of inner hair cells (IHCs), indicating a primary role for pejvakin in regulating OHC function and survival. Consistent with this model, synaptic transmission at the IHC ribbon synapse is largely unaffected in sirtaki mice that carry a C-terminal deletion mutation in Pjvk. Using the C-terminal domain of pejvakin as bait, we identified in a cochlear cDNA library ROCK2, an effector for the small GTPase Rho, and the scaffold protein IQGAP1, involved in modulating actin dynamics. Both ROCK2 and IQGAP1 associate via their coiled-coil domains with pejvakin. We conclude that pejvakin is required to sustain OHC activity and survival in a cell-autonomous manner likely involving regulation of Rho signaling.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers the State University of New Jersey, Piscataway, NJ 08854, United States.
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, NJ 08854, United States.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kazmierczak
authors.affiliation: Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany; Collaborative Research Center 889, University of Göttingen, 37099 Göttingen, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Pangršič
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers the State University of New Jersey, Piscataway, NJ 08854, United States.
authors.forename: Prahar
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers the State University of New Jersey, Piscataway, NJ 08854, United States.
authors.forename: Nadiya
authors.initials: N
authors.lastname: Chuchvara
authors.affiliation: Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany; Collaborative Research Center 889, University of Göttingen, 37099 Göttingen, Germany.
authors.forename: Alonso
authors.initials: A
authors.lastname: Barrantes-Freer
authors.affiliation: Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany; Collaborative Research Center 889, University of Göttingen, 37099 Göttingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Moser
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers the State University of New Jersey, Piscataway, NJ 08854, United States. Electronic address: schwander@biology.rutgers.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwander
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D018450:Disease Progression; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism / Q000473:pathology; D018072:Hair Cells, Auditory, Outer / Q000378:metabolism* / Q000473:pathology; D006367:HeLa Cells; D034381:Hearing Loss / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017384:Sequence Deletion; D013569:Synapses / Q000378:metabolism; D046509:Tissue Culture Techniques; D020703:ras GTPase-Activating Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D000094524:Gasdermins
chemical_list: D011506:Proteins; D012333:RNA, Messenger; D020703:ras GTPase-Activating Proteins; D054460:rho-Associated Kinases; C101203:IQ motif containing GTPase activating protein 1; C000605138:pejvakin protein, mouse; D000094524:Gasdermins; C515855:Rock2 protein, mouse
keywords: DFNB59; auditory neuropathy; hair cell; hearing loss; inner ear; pejvakin