Elsevier

Hearing Research

Volume 123, Issues 1–2, September 1998, Pages 125-136
Hearing Research

Combined cochleo-saccular and neuroepithelial abnormalities in the Varitint-waddler-J (VaJ) mouse

https://doi.org/10.1016/S0378-5955(98)00107-5Get rights and content

Abstract

Hearing loss in Varitint-waddler-J (VaJ) mice is of mixed origin with both cochleo-saccular and neuroepithelial components. Both VaJ/VaJ and VaJ/+ mutants show impaired cochlear function, but the homozygotes are more severely affected than heterozygotes. Neither group have any detectable compound action potential. Cochlear microphonics are only seen in half of the heterozygotes, at a reduced amplitude and raised threshold, and are not detected in any homozygotes. Summating potentials (SP) responses are seen in most of the heterozygotes, at high stimulus levels. The only responses in homozygotes were negative SPs seen in half of the mutants at very high sound levels, while the remaining homozygotes showed no responses to sound stimulation. Endocochlear potentials (EP) were often small or absent in both groups of mutants, with the homozygotes being more severely affected. Reduced pigmentation in the stria vascularis appears to be associated with a reduced EP, while a primary defect of the neuroepithelium, detectable by electron microscopy in hair cells of 14 day old mice, dramatically influences evoked potentials.

Introduction

Numerous mouse mutants with hearing defects are available as models for understanding human deafness (Steel, 1991, Steel, 1995). Functional and anatomical studies of the mouse and human inner ear have identified the same broad categories of pathology in the two species: morphogenetic, cochleo-saccular and neuroepithelial. Morphogenetic abnormalities involve gross structural deformities of the labyrinth. A strial abnormality is the primary cochleo-saccular defect in which there is a reduced or absent EP and sometimes collapse of Reissner's membrane, which eventually results in degeneration of the organ of Corti and spiral ganglion cells. Neuroepithelial defects originate in the organ of Corti and do not affect the stria directly (Steel and Bock, 1983a). Physiological and structural analyses of all these mouse mutants provides important information on the biological basis of normal hearing and genetic deafness. Unravelling the complexity of the inner ear has progressed more recently to identifying genes and their mutations which affect normal hearing (Steel and Brown, 1994). To date, 41 loci have been identified that are involved in non-syndromic deafness (Hereditary Hearing Impairment homepage http://dnalab.www.uia.ac.be/dnalab/hhh/). The full value of data emerging on the genetics of deafness derived from studies of mouse mutants and their human homologues will be maximized if it can be examined in the light of known functional and structural abnormalities of a particular mouse mutant.

The Varitint-waddler-J mouse (VaJ) arose as a semi-dominant mutation on chromosome 12 from the Va allele (Lane, 1972; Silvers, 1979). The Va mouse was first observed by Cloudman and Bunker (1945)in an outcross between C57 black and C57 brown stocks. Va/+ mice display a combination of spotting with dilution of coat colour and exhibit near normal viability. The homozygotes are white except for small patches of coloured hairs on the ears and tail base. Va/Va males are sterile and many mice of this genotype die before birth. All Va mice are deaf and show circling behaviour, head tossing and hyperactivity (Cools, 1972aCools, 1972b). Deol (1954)examining the inner ear morphology of Va/+ mice noted the first defects 4 days after birth. Anomalies of the tectorial membrane, followed by abnormalities in the spiral ganglion, organ of Corti and then strial atrophy are seen in the Va heterozygotes and homozygotes, characteristic of a neuroepithelial defect.

The effects of the VaJ mutation appear to be less severe than those associated with Va. VaJ/+ have only a slightly diluted coat colour (resembling Wv/+ mice). Both VaJ/+ and VaJ/VaJ are deaf but they behave normally and are fertile although a number of homozygotes die in utero (Lane, 1972). This study was undertaken to examine the physiological and structural abnormalities of the inner ear of VaJ mice.

Section snippets

Materials and methods

Mice carrying the VaJ allele on a C57BL/6/C3H F1 genetic background were obtained from the Jackson Laboratory, and a breeding colony established without the Hd mutation which originally was segregating in the supplied stock. Heterozygous mice were intercrossed to generate VaJ/VaJ, VaJ/+ and +/+ mice, easily distinguished by their coat colours. All control mice had a black coat, pigmented pinna, tail, and feet. Heterozygotes had a grey diluted coat colour and a white belly spot often with an

Electrophysiology

Both homozygous and heterozygous Varitint-waddler-J mutants show impaired cochlear responses. Furthermore, many of these mutants also show abnormally low endocochlear potentials, suggesting abnormal stria vascularis function. There is variability between individual mutants, as shown in Table 1A,B, but the homozygotes are more severely affected than the heterozygotes. Endocochlear potential measurements are shown in Fig. 1. Normal mice show a gradual increase in EP up to about two weeks after

Discussion

The physiological and structural studies reported here suggest that the Varitint-waddler-J mutant has an unusual combination of primary defects in both the neuroepithelium and the stria vascularis. The stria defect is variable, and in extreme cases there is no recordable EP associated with an absence of melanocytes in the stria. We have observed a similar strial pathology in other mouse mutants with coat colour defects (Cable et al., 1992, Cable et al., 1994) and the findings strongly suggest

Acknowledgements

We thank Mike Edel for technical assistance and N. Glenn for animal care.

References (34)

  • S.K Bosher et al.

    Observations on the histological features, development and pathogenesis of the inner ear degeneration of the deaf white cat

    Proc. R. Soc. London B

    (1965)
  • J Cable et al.

    Identification of two types of melanocyte within the stria vascularis of the mouse inner ear

    Pigment Cell Res.

    (1991)
  • J Cable et al.

    Effects of mutations at the W locus (c-kit) on inner ear pigmentation and function in the mouse

    Pigment Cell Res.

    (1994)
  • A.M Cloudman et al.

    The varitint-waddler mouse. A dominant mutation in Mus musculus

    J. Hered.

    (1945)
  • A.R Cools

    Neurochemical correlates of the waltzing-shaker syndrome in the varitint-waddler mouse

    Psychopharmacologia

    (1972)
  • A.R Cools

    Asymmetrical spotting and direction of circling in the varitint-waddler mouse

    J. Hered.

    (1972)
  • P Dallos et al.

    Cochlear summating potentials: Descriptive aspects

    Acta Otolaryngol. (Suppl.)

    (1972)
  • Cited by (41)

    • Pathophysiology of the cochlear intrastrial fluid-blood barrier (review)

      2016, Hearing Research
      Citation Excerpt :

      Restoration of strial vascular function may be effective in treating autoimmune hearing loss. Genetic defects in intrastrial fluid-blood barrier components have been identified in several genetically linked hearing loss pathologies, including Norrie Disease, Alport syndrome, Nr3b2(−/−) and Light (Blt) mutant, white spotting (Ws) and Varitint-waddler-J (VaJ) mouse mutants, and connexin 30 deficiency related hearing loss (Rehm et al., 2002; Cable and Steel, 1998, 1992, 1993; Chen and Nathans, 2007; Cohen-Salmon et al., 2007; Fujimura et al., 2005; Gratton et al., 2005; Kitamura et al., 1994; Kruegel et al., 2013; Ruan et al., 2005; Zallocchi et al., 2013). Norrie Disease presents with profound sensorineural deafness.

    • Constitutive activity of the human TRPML2 channel induces cell degeneration

      2010, Journal of Biological Chemistry
      Citation Excerpt :

      A milder phenotype is found in VaJ varitint-waddler mice, characterized by normal vestibular function, partial pigmentation deficiency, and partial hearing loss. These mice have been shown to express a second TRPML3 missense mutation, I362T, in cis to the severe A419P mutation (35, 40). When expressed alone, the I362T TRPML3 mutant has been shown to lack channel activity in a mammalian expression system; however, when expressed in cis with the A419P mutation, it has been suggested that I362T ameliorates the lethal effects of A419P by reducing cell surface expression of TRPML3 (20).

    • Genetic modifiers of hearing loss

      2016, Monographs in Human Genetics
    View all citing articles on Scopus
    View full text