Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation (pnas.org)
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 histamineactivated 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
Family Harbors a Dysfunctional mtDNA Variant.
We evaluated, assembled, and summarized the clinical data for the twogeneration pedigree.
The mother and all children present with various combinations of connective tissue manifestations, including Chiari malformation, cranial–cervical instability, hypermobility of joints, skin herniation, wound dehiscence, aortic valve disease, ankylosing spondylitis, fatigability, diabetes, and dysautonomic manifestations (SI Appendix).
The apparent matrilineal transmission of this complex array of clinical manifestations in all eight surviving offspring suggested an mtDNA disorder.