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Vestibular dysfunction, altered macular structure and trait localization in A/J inbred mice

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Abstract

A/J mice develop progressive hearing loss that begins before 1 month of age and is attributed to cochlear hair cell degeneration. Screening tests indicated that this strain also develops early onset vestibular dysfunction and has otoconial deficits. The purpose of this study was to characterize the vestibular dysfunction and macular structural pathology over the lifespan of A/J mice. Vestibular function was measured using linear vestibular evoked potentials (VsEPs). Macular structural pathology was evaluated using light microscopy, scanning electron microscopy, transmission electron microscopy, confocal microscopy and Western blotting. Individually, vestibular functional deficits in mice ranged from mild to profound. On average, A/J mice had significantly reduced vestibular sensitivity (elevated VsEP response thresholds and smaller amplitudes), whereas VsEP onset latency was prolonged compared to age-matched controls (C57BL/6). A limited age-related vestibular functional loss was also present. Structural analysis identified marked age-independent otoconial abnormalities in concert with some stereociliary bundle defects. Macular epithelia were incompletely covered by otoconial membranes with significantly reduced opacity and often contained abnormally large or giant otoconia as well as normal-appearing otoconia. Elevated expression of key otoconins (i.e., otoconin 90, otolin and keratin sulfate proteoglycan) ruled out the possibility of reduced levels contributing to otoconial dysgenesis. The phenotype of A/J was partially replicated in a consomic mouse strain (C57BL/6J-Chr 17A/J/NaJ), thus indicating that Chr 17A/J contained a trait locus for a new gene variant responsible to some extent for the A/J vestibular phenotype. Quantitative trait locus analysis identified additional epistatic influences associated with chromosomes 1, 4, 9 and X. Results indicate that the A/J phenotype represents a complex trait, and the A/J mouse strain presents a new model for the study of mechanisms underlying otoconial formation and maintenance.

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Acknowledgments

This work was supported by Grants from the National Institute on Deafness and Other Communication Disorders (DC006443 to SMJ and DC008603 to YWL). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Deafness and Other Communication Disorders or the National Institutes of Health. Special thanks to Kristal Mills for assistance with data collection, and Greg Tipton, Choongheon Lee and David Raybine for assistance with data analysis.

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  1. Jessica Pierce

    Present address: Department of Communication Sciences and Disorders, East Carolina University, Greenville, NC, 27858, USA

  2. Teresa E. Lever

    Present address: Department of Otolaryngology-Head and Neck Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA

Authors and Affiliations

  1. Department of Special Education and Communication Disorders, University of Nebraska-Lincoln, 301 Barkley Memorial Center, Lincoln, NE, 68583, USA

    Sarath Vijayakumar, Timothy A. Jones & Sherri M. Jones

  2. Genetics Department, Boys Town National Research Hospital, Omaha, NE, USA

    Xing Zhao & Yunxia Wang Lundberg

  3. The Jackson Laboratory, Bar Harbor, ME, USA

    David Bergstrom

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  1. Sarath Vijayakumar
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Correspondence to Timothy A. Jones.

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Vijayakumar, S., Lever, T.E., Pierce, J. et al. Vestibular dysfunction, altered macular structure and trait localization in A/J inbred mice. Mamm Genome 26, 154–172 (2015). https://doi.org/10.1007/s00335-015-9556-0

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