Mitochondrial haplogroup H correlates with ATP levels and age at onset in Huntington disease

作者：Arning Larissa^*; Haghikia Aiden; Taherzadeh Fard Elahe; Saft Carsten; Andrich Juergen; Pula Bartoz; Hoextermann Stefan; Wieczorek Stefan; Akkad Denis Amer; Perrech Moritz; Gold Ralf; Epplen Joerg Thomas; Chan Andrew

来源：Journal of Molecular Medicine-JMM, 2010, 88(4): 431-436.

DOI：10.1007/s00109-010-0589-2

• Huntington disease
• Age at onset
• mtDNA haplogroups
• ATP

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-1alpha 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.

• 出版日期2010-4