A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice

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, ye t some individuals with these mutations have severe hearing loss, whereas t heir maternal relatives with the identical mtDNA mutation have normal heari ng(1,2). Epidemiologic, biochemical and genetic data indicate that nuclear genes are often the main determinants of these differences in phenotype(3-5 ). To identify a mouse model for maternally inherited hearing loss, we scre ened reciprocal backcrosses of three inbred mouse strains, A/J. NOD/LtJ and SKH2/J, with age-related hearing loss (AHL). In the (A/JxCAST/Ei)xA/J back cross. mtDNA derived from the A/J strain exerted a significant detrimental effect on hearing when compared with mtDNA from the CAST/Ei strain. This ef fect was not seen in the (NOD/LtJ xCAST/Ei)xNOD/LtJ and (SKH2/JxCAST/Ei)xSK H2/J backcrosses. Genotyping revealed that this effect was seen only in mic e homozygous for the A/J allele at the Ahl locus on mouse chromosome 10. Se quencing of the mitochondrial genome in the three inbred strains revealed a single nucleotide insertion in the fRNA-Arg gene (mt-Tr) as the probable m ediator of the mitochondrial effect. This is the first mouse model with a n aturally occurring mtDNA mutation affecting a clinical phenotype, and it pr ovides an experimental model to dissect the pathophysiologic processes conn ecting mtDNA mutations to hearing loss.