Vestibular Dysfunction, Altered Macular Structure and Trait Localization in A/J Inbred Mice

Authors

Sarath Vijayakumar, University of Nebraska - LincolnFollow
Teresa E. Lever, University of Missouri School of Medicine
Jessica Pierce, East Carolina University
Xing Zhao, Boys Town National Research Hospital
David Bergstrom, The Jackson Laboratory
Yunxia Wang Lundberg, Boys Town National Research Hospital
Timothy A. Jones, University of Nebraska - LincolnFollow
Sherri M. Jones, University of Nebraska - LincolnFollow

Document Type

Article

Date of this Version

4-2015

Citation

Mammalian Genome (April 2015) 26(3-4): 154–172. DOI: 10.1007/s00335-015-9556-0.

Comments

Copyright 2015, International Mammalian Genome Society. Used by permission.

Abstract

A/J mice develop progressive hearing loss that begins before one month of age and is attributed to cochlear hair cell degeneration. Screening tests indicated 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, SEM, TEM, 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 agematched controls (C57BL/6J). 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 17^A/J/NaJ), thus indicating that Chr 17^A/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.