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A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice

Nature Genetics volume 27, pages 191–194 (2001)Cite this article

Abstract

The pathophysiologic pathways and clinical expression of mitochondrial DNA (mtDNA) mutations are not well understood. This is mainly the result of the heteroplasmic nature of most pathogenic mtDNA mutations and of the absence of clinically relevant animal models with mtDNA mutations. mtDNA mutations predisposing to hearing impairment in humans are generally homoplasmic, yet some individuals with these mutations have severe hearing loss, whereas their maternal relatives with the identical mtDNA mutation have normal hearing1,2. Epidemiologic, biochemical and genetic data indicate that nuclear genes are often the main determinants of these differences in phenotype3,4,5. To identify a mouse model for maternally inherited hearing loss, we screened reciprocal backcrosses of three inbred mouse strains, A/J, NOD/LtJ and SKH2/J, with age-related hearing loss (AHL). In the (A/J×CAST/Ei)×A/J backcross, mtDNA derived from the A/J strain exerted a significant detrimental effect on hearing when compared with mtDNA from the CAST/Ei strain. This effect was not seen in the (NOD/LtJ ×CAST/Ei)×NOD/LtJ and (SKH2/J×CAST/Ei)×SKH2/J backcrosses. Genotyping revealed that this effect was seen only in mice homozygous for the A/J allele at the Ahl locus on mouse chromosome 10. Sequencing of the mitochondrial genome in the three inbred strains revealed a single nucleotide insertion in the tRNA-Arg gene (mt-Tr) as the probable mediator of the mitochondrial effect. This is the first mouse model with a naturally occurring mtDNA mutation affecting a clinical phenotype, and it provides an experimental model to dissect the pathophysiologic processes connecting mtDNA mutations to hearing loss.

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Figure 1: Frequency distribution of auditory-evoked brainstem response (ABR) thresholds in (A/J×CAST/Ei)×A/J backcross progeny.
Figure 2: Evolutionary comparison and two-dimensional structure of mouse mt-Tr.
Figure 3: Comparison of age-related hearing loss among A/J, A/HeJ and A/WySnJ inbred strains of mice.

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Acknowledgements

This work was supported by grants and a contract from the National Institutes of Health/National Institute of Deafness and Other Communication Disorders. Jackson Laboratory institutional shared services are supported by a National Cancer Institute support grant.

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Authors and Affiliations

  1. The Jackson Laboratory, Bar Harbor, Maine, USA

    Kenneth R. Johnson & Qing Y Zheng

  2. Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Medical Genetics Birth Defects Center, The Cedars-Sinai Medical Center Burns and Allen Research Institute and UCLA School of Medicine, Los Angeles, California, USA

    Yelena Bykhovskaya, Olga Spirina & Nathan Fischel-Ghodsian

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  1. Kenneth R. Johnson
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Correspondence to Nathan Fischel-Ghodsian.

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Johnson, K., Y Zheng, Q., Bykhovskaya, Y. et al. A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice. Nat Genet 27, 191–194 (2001). https://doi.org/10.1038/84831

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