title: Mitochondrial haplogroup H correlates with ATP levels and age at onset in Huntington disease.
abstract: Mitochondrial dysfunction has been implicated in the pathogenesis of Huntington disease (HD), a primarily neurodegenerative disorder that results from an expansion in the polymorphic trinucleotide CAG tract in the HD gene. In order to evaluate whether mitochondrial DNA (mtDNA) variation contributes to HD phenotype we genotyped 13 single nucleotide polymorphisms (SNPs) that define the major European mtDNA haplogroups in 404 HD patients. Genotype-dependent functional effects on intracellular ATP concentrations were assessed in peripheral leukocytes. In patients carrying the most common haplogroup H (48.3%), we demonstrate a significantly lower age at onset (AO). In combination with PGC-1 alpha genotypes, 3.8% additional residual variance in HD AO can be explained. Intracellular ATP concentrations in HD patients carrying the cytochrome c oxidase subunit I (CO1) 7028C allele defining haplogroup H were significantly higher in comparison to non-H individuals (mean +/- SEM, 599 +/- 51.8 ng/ml, n = 14 vs. 457.5 +/- 40.4 ng/ml, p = 0.03, n = 9). In contrast, ATP concentrations in cells of HD patients independent from mtDNA haplogroup showed no significant differences in comparison to matched healthy controls. Our data suggest that an evolutionarily advantageous mitochondrial haplogroup is associated with functional mitochondrial alterations and may modify disease phenotype in the context of neurodegenerative conditions such as HD.
authors.affiliation: Department of Human Genetics, Ruhr-University, 44780, Bochum, Germany. larissa.arning@rub.de
authors.forename: Larissa
authors.initials: L
authors.lastname: Arning
authors.forename: Aiden
authors.initials: A
authors.lastname: Haghikia
authors.forename: Elahe
authors.initials: E
authors.lastname: Taherzadeh-Fard
authors.forename: Carsten
authors.initials: C
authors.lastname: Saft
authors.forename: Jürgen
authors.initials: J
authors.lastname: Andrich
authors.forename: Bartoz
authors.initials: B
authors.lastname: Pula
authors.forename: Stefan
authors.initials: S
authors.lastname: Höxtermann
authors.forename: Stefan
authors.initials: S
authors.lastname: Wieczorek
authors.forename: Denis Amer
authors.initials: DA
authors.lastname: Akkad
authors.forename: Moritz
authors.initials: M
authors.lastname: Perrech
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Jörg Thomas
authors.initials: JT
authors.lastname: Epplen
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D004272:DNA, Mitochondrial / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D004272:DNA, Mitochondrial; D000255:Adenosine Triphosphate