title: Slc26a4 expression prevents fluctuation of hearing in a mouse model of large vestibular aqueduct syndrome.
abstract: SLC26A4 mutations cause fluctuating and progressive hearing loss associated with enlargement of the vestibular aqueduct (EVA). SLC26A4 encodes a transmembrane anion exchanger called pendrin expressed in nonsensory epithelial cells of the lateral wall of cochlea, vestibular organs and endolymphatic sac. We previously described a transgenic mouse model of EVA with doxycycline (dox)-inducible expression of Slc26a4 in which administration of dox from conception to embryonic day 17.5 (DE17.5) resulted in hearing fluctuation between 1 and 3months of age. In the present study, we hypothesized that Slc26a4 is required to stabilize hearing in DE17.5 ears between 1 and 3months of age. We tested our hypothesis by evaluating the effect of postnatal re-induction of Slc26a4 expression on hearing. Readministration of dox to DE17.5 mice at postnatal day 6 (P6), but not at 1month of age, resulted in reduced click-evoked auditory brainstem response (ABR) thresholds, less fluctuation of hearing and a higher surface density of pendrin expression in spindle-shaped cells of the stria vascularis. Pendrin expression in spindle-shaped cells was inversely correlated with ABR thresholds. These findings suggest that stabilization of hearing by readministration of dox at P6 is mediated by pendrin expression in spindle-shaped cells. We conclude that early re-induction of Slc26a4 expression can prevent fluctuation of hearing in our Slc26a4-insufficient mouse model. Restoration of SLC26A4 expression and function could reduce or prevent fluctuation of hearing in EVA patients.
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nishio
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: Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Mouse Auditory Testing Core Facility, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Fitzgerald
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 / Q000008:administration & dosage* / Q000172:deficiency* / Q000235:genetics; D003051:Cochlea / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004712:Endolymphatic Sac / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D015316:Genetic Therapy; D006309:Hearing / Q000502:physiology; D006319:Hearing Loss, Sensorineural / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000076988:Sulfate Transporters; D013997:Time Factors; D014723:Vestibular Aqueduct / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology
chemical_list: D027321:Anion Transport Proteins; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters
keywords: DFNB4; EVA; SLC26A4; deafness; fluctuation; gene therapy