TY - JOUR
T1 - Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation
AU - Schaefer, Patrick M.
AU - Alves, Leonardo Scherer
AU - Lvova, Maria
AU - Huang, Jessica
AU - Rathi, Komal
AU - Janssen, Kevin
AU - Butic, Arrienne
AU - Yardeni, Tal
AU - Morrow, Ryan
AU - Lott, Marie
AU - Murdock, Deborah
AU - Song, Angela
AU - Keller, Kierstin
AU - Garcia, Benjamin A.
AU - Francomano, Clair A.
AU - Wallace, Douglas C.
N1 - Publisher Copyright:
Copyright © 2022 the Author(s).
PY - 2022/11/8
Y1 - 2022/11/8
N2 - 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.
AB - 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.
KW - connective tissue disorder
KW - histamine signaling
KW - mitochondrial disorder
KW - mtDNA haplogroups
UR - http://www.scopus.com/inward/record.url?scp=85141196668&partnerID=8YFLogxK
U2 - 10.1073/pnas.2212417119
DO - 10.1073/pnas.2212417119
M3 - Article
C2 - 36322731
AN - SCOPUS:85141196668
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
M1 - e2212417119
ER -