The phenotype modifier: is the mitochondrial DNA background responsible for individual differences in disease severity
Year: 2019
Type: editorial
Abstract: Penetrance of mutations and phenotypic expression in inborn errors of metabolism is highly variable in individuals carrying the same pathogenic genetic variants, even between individuals from the same family. This variability has been hypothesized to be a consequence of other (epi)genetic variants in the same gene, additional genomic variants, different environmental factors (e.g., change in the cellular concentration of trace elements, pH, etc.), affecting posttranslational modification, trafficking and the final cellular localization or environment of the encoded proteins. But does our mitochondrial DNA (mtDNA) play a crucial role in the phenotypic expression and severity of different disorders, like inborn errors of metabolism1? We have emerging data with respect to the relevance of the mitochondrial background (mtDNA genomic variations) in the population. In addition, there is also scientific evidence on the significance of mtDNA genomic variations mediating disease expression in Mendelian disorders2. Nonpathogenic variants in mitochondrial genes have been shown to have a very important role in health and disease. The effect on body composition, gene expression and metabolism of different mitochondrial and nuclear genetic background combinations has been demonstrated in the Mitochondrial-Nuclear eXchange mice3. Several studies proposed interaction and correlation between mitochondrial single nucleotide polymorphisms and nuclear variants in psychiatric disorders, like bipolar disease,4 with respect to disease onset or severity. Other examples for population-based risk modifiers are the mitochondrial haplogroups. The Asian haplogroup N9a was found to be associated with a decreased risk of type II diabetes mellitus.5, 6 Another example is the European haplogroup J and T,7, 8 associated with decreased incidence of Alzheimer and Parkinson disease, while haplogroup H and more specifically haplogroup H5a bearing the tRNAGln MT-TQ m.4336G > A variant is associated with increased risk of Alzheimer and Parkinson Disease.9, 10 Haplogroups are surely important for the health risk of a given population at a given geographic location, but are mitochondrial variants important in defining disease severity in individual patients as well? One of the long known examples of mitochondrial phenotype-modifier variants are mtDNA variants, modifying the expression of primary Leber hereditary optic atrophy (LHON)-associated mtDNA mutations. The three most common LHON mutations are common examples; including the LHON mutations MT-ND1 m.3460G > A (p.Ala52Thr),11 the MT-ND4 m.11778G > A (p.Arg340His),12 and MT-ND6 m.14484 T > C p.Met64Val)13 in decreasing order of the severity of the associated mitochondrial complex I defect. However, the milder the complex I defect, the more likely that the penetrance of the primary mutation will be enhanced by occurring on mtDNA haplogroup J.14-16 A very different example is an interaction between the mitochondrial and nuclear DNA. Patients with homozygous c.523delC mutations in SLC25A4 have highly variable phenotype, including lethal cardiomyopathy, correlating with the mitochondrial DNA background in patients.17 The presence of the variant ND6P25L in a mouse model of slc25a4−/− increased the severity of cardiomyopathy suggesting nuclear-mitochondrial crosstalk in the nucleotide transporter disease.18 This raises the question whether inter-individual differences between patients carrying the same mutations could be due to their different mitochondrial background. Mitochondrial DNA is a unique, highly variable genetic background, which has been shown to affect population disease risk, and, in certain disorders, it might affect individual disease severity. The strong metabolic interlink between most inborn errors of metabolism and mitochondria suggests multiple regulatory mechanisms associated with the mitochondrial genome, affecting intact and altered metabolism. We propose to evaluate the role of the mitochondrial genetic background beyond “variant and disease risk” associations. We propose that the presence of a specific variant or haplogroup could be related to the expression and severity of a given non-mitochondrial disease. Finding the potential role of the mitochondrial genetic background in metabolic disorders will lead to a better understanding of phenotypic variability, and variable expression of nuclear coded mutations causing Mendelian disease. It will also lead to new therapeutic ideas tailored to the needs of the individual patient.
DOI: 10.1002/jimd.12050
Authors: Eva Morava, Tamas Kozicz, Douglas C Wallace
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2914100826