Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation

Patrick M. Schaefer, Leonardo Scherer Alves, Maria Lvova, Jessica Huang, Komal Rathi, Kevin Janssen, Arrienne Butic, Tal Yardeni, Ryan Morrow, Marie Lott, Deborah Murdock, Angela Song, Kierstin Keller, Benjamin A. Garcia, Clair A. Francomano, Douglas C. Wallace

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish
Article numbere2212417119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number45
StatePublished - Nov 8 2022


  • connective tissue disorder
  • histamine signaling
  • mitochondrial disorder
  • mtDNA haplogroups


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