title: Progressive Hearing Loss in Mice Carrying a Mutation in Usp53.
abstract: Disordered protein ubiquitination has been linked to neurodegenerative disease, yet its role in inner ear homeostasis and hearing loss is essentially unknown. Here we show that progressive hearing loss in the ethylnitrosourea-generated mambo mouse line is caused by a mutation in Usp53, a member of the deubiquitinating enzyme family. USP53 contains a catalytically inactive ubiquitin-specific protease domain and is expressed in cochlear hair cells and a subset of supporting cells. Although hair cell differentiation is unaffected in mambo mice, outer hair cells degenerate rapidly after the first postnatal week. USP53 colocalizes and interacts with the tight junction scaffolding proteins TJP1 and TJP2 in polarized epithelial cells, suggesting that USP53 is part of the tight junction complex. The barrier properties of tight junctions of the stria vascularis appeared intact in a biotin tracer assay, but the endocochlear potential is reduced in adult mambo mice. Hair cell degeneration in mambo mice precedes endocochlear potential decline and is rescued in cochlear organotypic cultures in low potassium milieu, indicating that hair cell loss is triggered by extracellular factors. Remarkably, heterozygous mambo mice show increased susceptibility to noise injury at high frequencies. We conclude that USP53 is a novel tight junction-associated protein that is essential for the survival of auditory hair cells and normal hearing in mice, possibly by modulating the barrier properties and mechanical stability of tight junctions.
  
  
  CONCLUSIONS
  Hereditary hearing loss is extremely prevalent in the human population, but many genes linked to hearing loss remain to be discovered. Forward genetics screens in mice have facilitated the identification of genes involved in sensory perception and provided valuable animal models for hearing loss in humans. This involves introducing random mutations in mice, screening the mice for hearing defects, and mapping the causative mutation. Here, we have identified a mutation in the Usp53 gene that causes progressive hearing loss in the mambo mouse line. We demonstrate that USP53 is a catalytically inactive deubiquitinating enzyme and a novel component of tight junctions that is necessary for sensory hair cell survival and inner ear homeostasis.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kazmierczak
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: National Institute of Health and Medical Research, Unit 1051, Institute for Neurosciences of Montpellier, F-34091 Montpellier, France, and.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kazmierczak
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Prahar
authors.identifier: http://orcid.org/0000-0001-6201-852X
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Valentin
authors.initials: V
authors.lastname: Starovoytov
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Ohlemiller
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: D000595:Amino Acid Sequence; D000818:Animals; D003051:Cochlea / Q000473:pathology; D018450:Disease Progression; D005260:Female; D057809:HEK293 Cells; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology*; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D064570:Ubiquitin-Specific Proteases / Q000235:genetics*
chemical_list: C579192:USP53 protein, human; D064570:Ubiquitin-Specific Proteases
keywords: Usp53; hearing loss; inner ear; mambo mice; tight junction; ubiquitin