title: Slc26a4-insufficiency causes fluctuating hearing loss and stria vascularis dysfunction.
abstract: SLC26A4 mutations can cause a distinctive hearing loss phenotype with sudden drops and fluctuation in patients. Existing Slc26a4 mutant mouse lines have a profound loss of hearing and vestibular function, with severe inner ear malformations that do not model this human phenotype. In this study, we generated Slc26a4-insufficient mice by manipulation of doxycycline administration to a transgenic mouse line in which all Slc26a4 expression was under the control of doxycycline. Doxycycline was administered from conception to embryonic day 17.5, and then it was discontinued. Auditory brainstem response thresholds showed significant fluctuation of hearing loss from 1 through 3months of age. The endocochlear potential, which is required for inner ear sensory cell function, correlated with auditory brainstem response thresholds. We observed degeneration of stria vascularis intermediate cells, the cells that generate the endocochlear potential, but no other abnormalities within the cochlea. We conclude that fluctuations of hearing result from fluctuations of the endocochlear potential and stria vascularis dysfunction in Slc26a4-insufficient mouse ears. This model can now be used to test potential interventions to reduce or prevent sudden hearing loss or fluctuation in human patients. Our strategy to generate a hypomorphic mouse model utilizing the tet-on system will be applicable to other diseases in which a hypomorphic allele is needed to model the human phenotype.
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Taku
authors.initials: T
authors.lastname: Ito
authors.affiliation: Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Li
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Kurima
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Byung Yoon
authors.initials: BY
authors.lastname: Choi
authors.affiliation: Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Philine
authors.initials: P
authors.lastname: Wangemann
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: griffita@nidcd.nih.gov.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Griffith
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D001309:Auditory Threshold; D003051:Cochlea / Q000473:pathology / Q000503:physiopathology; D004318:Doxycycline; D016057:Evoked Potentials, Auditory, Brain Stem; D015870:Gene Expression; D006198:Hair Cells, Auditory / Q000473:pathology / Q000502:physiology; D034381:Hearing Loss / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D017084:Otoacoustic Emissions, Spontaneous; D060888:Real-Time Polymerase Chain Reaction; D013316:Stria Vascularis / Q000473:pathology / Q000502:physiology*; D000076988:Sulfate Transporters
chemical_list: D027321:Anion Transport Proteins; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; D004318:Doxycycline
keywords: Conditional; Doxycycline; Endocochlear potential; Fluctuation; Hearing loss; Hypomorph; Inducible; SLC26A4; Stria vascularis; Transgenic; Vestibular aqueduct