A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice

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 hearing. Epidemiologic, biochemical and genetic data indicate that nuclear genes are often the main determinants of these differences in phenotype. 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 x CAST/Ei) x 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 x CAST/Ei) x NOD/LtJ and (SKH2/J x CAST/Ei) x 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.

mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes

“…The polymorphism in the mt genome-encoded Cox3 subunit (Table 3) is an unlikely contributor, as the resistant ALR genome shares this substitution with the NOD genome. The significance of the polymorphisms in the mt-Tr gene (Table 3) is presently unclear; this mt gene was not demonstrated to be interactive with nuclear genes (Ahl1, Ahl2) contributing to hearing loss in a NOD×CAST cross [21,24]. Interestingly, however, the normally hearing NON/Lt strain shares the 8-bp polyA polymorphism with the normally hearing CAST/Ei strain.…”

“…An adenine insertion in a polyadenine repeat in the mitochondrial arginyl tRNA (mt-Tr) gene of the A/J mt genome was associated with this strain's hearing impairment. The mt tRNA-Arg association was not demonstrated in outcrosses between CAST/Ei and NOD [21], yet NOD, ALR, and ALS, but not NON, all exhibit the age-related hearing loss phenotype [22]. In addition to sharing the pathogenic Ahl1 allele with A/J on Chr.…”

“…10, designated Ahl, that produced a maternally inherited, age-related hearing loss [21]. An adenine insertion in a polyadenine repeat in the mitochondrial arginyl tRNA (mt-Tr) gene of the A/J mt genome was associated with this strain's hearing impairment.…”

Ageing and hearing loss

“…Both the time of onset and the rate of progression of HL in Cdh23 753A homozygotes depend on the effects of strain-specific genetic factors [43]. A number of genes or loci have been identified as Cdh23 modifiers, including the mitochondrial mutation in the tRNA-Arg gene (mtTr 9827ins8 ) (as in A/J) [44], ahl2 (as in NOD/LtJ) [45]; and ahl3 [46]. A combination of either one of these 'accelerating alleles' with homozygosity for Cdh23 753A has been shown to exacerbate HL.…”

Prévenir la transmission des mutations de l’ADN mitochondrial par don de cytoplasme : où en est-on ?

“…Pourtant ce dialogue a déjà été mis en cause dans l'expression phénotypique d'une mutation localisée dans un gène nucléaire. Le phénotype « surdité » de souris mutées dans le gène Ahl (age-related hearing loss gene), ne s'exprime en effet qu'en cas de co-mutation touchant un gène mitochondrial codant l'ARNt-Arg [14]. Chez l'humain, la pénétrance 3 incomplète des mutations de l'ADNmt responsables de la neuropathie optique de Leber 4 , serait liée à l'existence d'un ou plusieurs gènes nucléaires modificateurs localisés sur le chromosome X [15].…”