title: Progressive irreversible hearing loss is caused by stria vascularis degeneration in an Slc26a4-insufficient mouse model of large vestibular aqueduct syndrome.
abstract: Hearing loss of patients with enlargement of the vestibular aqueduct (EVA) can fluctuate or progress, with overall downward progression. The most common detectable cause of EVA is mutations of SLC26A4. We previously described a transgenic Slc26a4-insufficient mouse model of EVA in which Slc26a4 expression is controlled by doxycycline administration. Mice that received doxycycline from conception until embryonic day 17.5 (DE17.5; doxycycline discontinued at embryonic day 17.5) had fluctuating hearing loss between 1 and 6 months of age with an overall downward progression after 6 months of age. In this study, we characterized the cochlear functional and structural changes underlying irreversible hearing loss in DE17.5 mice at 12 months of age. The endocochlear potential was decreased and inversely correlated with auditory brainstem response thresholds. The stria vascularis was thickened and edematous in ears with less severe hearing loss, and thinned and atrophic in ears with more severe hearing loss. There were pathologic changes in marginal cell morphology and gene expression that were not observed at 3 months. We conclude that strial dysfunction and degeneration are the primary causes of irreversible progressive hearing loss in our Slc26a4-insufficient mouse model of EVA. This model of primary strial atrophy may be used to explore the mechanisms of progressive hearing loss due to strial dysfunction.
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ito
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nishio
authors.affiliation: Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: P
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: A J
authors.initials: AJ
authors.lastname: Griffith
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D001309:Auditory Threshold / Q000502:physiology; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D006198:Hair Cells, Auditory / Q000473:pathology; D034381:Hearing Loss / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D013316:Stria Vascularis / Q000473:pathology*; D000076988:Sulfate Transporters; D014723:Vestibular Aqueduct / Q000473:pathology; D015837:Vestibular Diseases / Q000150:complications* / Q000235:genetics*; D000098854:Kcnj10 Channel
chemical_list: D027321:Anion Transport Proteins; D051657:KCNQ1 Potassium Channel; D000098854:Kcnj10 Channel; C496910:Kcnq1 protein, mouse; D024661:Potassium Channels, Inwardly Rectifying; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters
keywords: SLC26A4; deafness; doxycycline; fluctuation; hypomorphic; stria vascularis