mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A > G mitochondrial disease

作者：Grady John P; Pickett Sarah J; Ng Yi Shiau; Alston Charlotte L; Blakely Emma L; Hardy Steven A; Feeney Catherine L; Bright Alexandra A; Schaefer Andrew M; Gorman Grainne S; McNally Richard J Q; Taylor Robert W; Turnbull Doug M; McFarland Robert^*

来源：EMBO Molecular Medicine, 2018, 10(6): UNSP e8262.

DOI：10.15252/emmm.201708262

• m.3243A > G
• MELAS
• mitochondrial disease
• mtDNA copy number
• mtDNA heteroplasmy

Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N=231, urine N=235, skeletal muscle N=77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine (R-2=0.61-0.73). Blood heteroplasmy declines by similar to 2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and similar to 20% higher m.3243A>G mutation load; we present formulas to adjust for this. Blood is the most highly correlated mutation measure for disease burden and progression in m.3243A>G-harbouring individuals; increasing age and heteroplasmy contribute (R-2=0.27, P<0.001). In muscle, heteroplasmy, age and mtDNA copy number explain a higher proportion of variability in disease burden (R-2=0.40, P<0.001), although activity level and disease severity are likely to affect copy number. Whilst our data indicate that age-corrected blood m.3243A>G heteroplasmy is the most convenient and reliable measure for routine clinical assessment, additional factors such as mtDNA copy number may also influence disease severity.

• 出版日期2018-6