Mitochondrial DNA Variation and Heteroplasmy in Monozygotic Twins Clinically Discordant for Multiple Sclerosis.
We examined the debated link between mitochondrial DNA (mtDNA) variation and multiple sclerosis (MS) using 49 monozygotic (MZ) twin pairs clinically discordant for MS, which enables to associate de novo mtDNA variants, skewed heteroplasmy, and mtDNA copy number with MS manifestation. Ultra-deep sequencing of blood-derived mtDNA revealed 25 heteroplasmic variants with potentially pathogenic features in 18 pairs. All variants were pair-specific and had low and/or similar heteroplasmy levels in both cotwins. In one pair, a confirmed pathogenic variant (m.11778G>A, heteroplasmy ∼50%) associated with Leber hereditary optic neuropathy was detected. Detailed diagnostic investigation revealed subclinical MS signs in the prior nondiseased cotwin. Moreover, neither mtDNA deletions nor copy-number variations were involved. Furthermore, the majority of heteroplasmic variants were shared among MZ twins and exhibited more similar heteroplasmy levels in the same tissue of MZ twins as compared with different tissues of the same individual. Heteroplasmy levels were also more similar within MZ twins compared with nonidentical siblings. Our analysis excludes mtDNA variation as a major driver of the discordant clinical manifestation of MS in MZ twins, and provides valuable insights into the occurrence and distribution of heteroplasmic variants within MZ twins and nonidentical siblings, and across different tissues.
Department of Genetics/Epigenetics, Saarland University, Saarbrücken, Germany.
Nicole Y P
NY
Souren
Institute of Clinical Neuroimmunology, Medical Campus Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany.
Lisa A
LA
Gerdes
Institute of Clinical Neuroimmunology, Medical Campus Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany.
Tania
T
Kümpfel
Department of Genetics/Epigenetics, Saarland University, Saarbrücken, Germany.
Pavlo
P
Lutsik
Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-Universität München, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
Thomas
T
Klopstock
Institute of Clinical Neuroimmunology, Medical Campus Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Reinhard
R
Hohlfeld
Department of Genetics/Epigenetics, Saarland University, Saarbrücken, Germany.
Jörn
J
Walter
D000328:Adult; D000368:Aged; D004272:DNA, Mitochondrial / Q000235:genetics*; D004200:Diseases in Twins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014430:Twins, Monozygotic / Q000235:genetics*; D055815:Young Adult
D004272:DNA, Mitochondrial
LHON; heteroplasmy; monozygotic twins; mtDNA; multiple sclerosis