Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation 2022 Schaefer et al

Significance

Here we demonstrate a previously unreported class of mitochondrial disease originating from the incompatibility of common mtDNA variants. Until now, clinical evaluation of the mitochondrial DNA only assessed the frequency of individual variants, and common variants were considered nonpathogenic. Our findings emphasize that common mtDNA variants can cause mitochondrial disease when arising on an uncommon mtDNA background. Thus, idiopathic primary mitochondrial disease patients should be checked for novel combinations of otherwise common variants which may contribute to the etiology of the disorder.

Abstract

Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising on the mtDNA haplogroup H7A background, an extremely rare combination. Analysis of transmitochondrial cybrids with the 13708A-H7 mtDNA revealed a lower mitochondrial respiration, increased reactive oxygen species production (mROS), and dysregulation of connective tissue gene expression. The mitochondrial dysfunction was exacerbated by histamine, explaining why all eight surviving children inherited the dysfunctional histidine decarboxylase allele (W327X) from the father. Thus, certain combinations of common mtDNA variants can cause mitochondrial dysfunction, mitochondrial dysfunction can affect extracellular matrix gene expression, and histamine-activated mROS production can augment the severity of mitochondrial dysfunction. Most important, we have identified a previously unreported genetic cause of mitochondrial disorder arising from the incompatibility of common, nonpathogenic mtDNA variants.

Open access, https://www.pnas.org/doi/10.1073/pnas.2212417119