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Mitonuclear epistasis and mitochondrial disease
Mitochondrion ( IF 4.4 ) Pub Date : 2017-07-01 , DOI: 10.1016/j.mito.2017.06.001 Edward H Morrow 1 , M Florencia Camus 2
Mitochondrion ( IF 4.4 ) Pub Date : 2017-07-01 , DOI: 10.1016/j.mito.2017.06.001 Edward H Morrow 1 , M Florencia Camus 2
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Wang et al. (2015) report the joint effect of genetic variants in both the nuclear and mitochondrial DNA (mtDNA) on the occurrence of Kallmann syndrome in a large Han Chinese family. The nuclear variant (KAL1 c.146G > T, p.Cys49Phe) is not expected to cause changes to protein structure or function. Although the pathogenicity of the mitochondrial variant (tRNA, m.5800A > G) has been predicted (Bannwarth et al., 2013), there is no empirical evidence to support that prediction and it was not found to depress cellular oxidative phosphorylation (Wang et al., 2015). Their interpretation is that the two point mutations act synergistically, causing abnormal migration of gonadotropin-releasing hormone neurons, which is thought to be the underlying mechanism for this developmental disorder. Since mutations in both genomes are required for manifestation of the phenotype, their results challenge how mitochondrial disease may be defined. We suggest that this two-locus/genome model of mitochondrial disease phenotypes may apply more broadly than is currently appreciated. Although the action of genetic background or modifiers have been implicated in altering the penetrance of primary pathological mutations underlying mitochondrial disease, reviews of this evidence have focused on specific disease sub-types (Bénit et al., 2010). Here, a review of the published evidence from the medical literature suggest that mitonuclear epistatic interactions are widespread and make a significant contribution to the variability in disease penetrance, which is a widely reported feature of mitochondrial pathologies (Limongelli et al., 2004). We have identified 15 loci in mtDNA where the pathogenic effect (spanning a number of different mitochondrial diseases) is dependent upon the nuclear background, specific nuclear polymorphic sites, or expression levels of nuclear genes (Table 1). In most cases, the defect in the mtDNA can be modified by multiple different nuclear loci, although some ‘master modifiers’ appear capable of influencing multiple mtDNA mutations (e.g. VARS2, LARS2). A further 11 nuclear loci have been identified where mitochondrial haplotype (or variants) have modified the pathogenic phenotype, which includes type II diabetes, Parkinson's and Alzheimer's disease as well as classical mitochondrial diseases. Only 6 of these loci co-localize to mitochondria. In one example, the deleterious effect of the m.5703G > A mutation in human cell lines disappeared after a period of time in culture (Hao et al., 1999). However, replacement of the nuclear background (using cybrids) reintroduced the deleterious phenotype. These data support a compensatory model of evolution within the nuclear genome in response to the presence of deleterious mutations within the mitochondrial genome. Together these studies highlight the potential role of mitonuclear epistasis in the expression and penetrance of human mitochondrial disease. We declare no competing interests. Funding has been provided to EHM by a Royal Society University Research Fellowship and the European Research Council (#280632). MFC was supported by the European Research Council under the Marie Skłodowska-Curie Actions (#708362).
更新日期：2017-07-01
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