Journal Article

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

Hardy, Steven A, Turnbull, Doug M, Gorman, Gráinne S, Schaefer, Andrew M, Ng, Yi Shiau, Bright, Alexandra A, Feeney, Catherine L, Taylor, Robert W, Grady, John P, Blakely, Emma L, McNally, Richard JQ, McFarland, Robert, Pickett, Sarah J, Alston, Charlotte L

2018

Overview

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 ~2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and ~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. Synopsis The m.3243A>G pathogenic mtDNA variant is associated with a highly heterogeneous multisystem disorder and varying mutation levels across tissues. In this study, mutation levels were characterised in three commonly sampled tissues ‐ blood, urine, skeletal muscle ‐ and correlated with disease burden. Urine m.3243A>G heteroplasmy levels display more variability than blood levels and must be corrected for a ˜20% lower level in females. Blood m.3243A>G heteroplasmy levels must be corrected for a decline of ˜2.3% per year. Disease burden and progression are more strongly associated with blood m.3243A>G heteroplasmy levels than urine levels. 27% of the variance in disease burden can be attributed to blood m.3243A>G heteroplasmy and age. Age, m.3243A>G heteroplasmy level and mtDNA copy number in skeletal muscle explain 40% of the variance in disease burden. Graphical Abstract The m.3243A>G pathogenic mtDNA variant is associated with a highly heterogeneous multisystem disorder and varying mutation levels across tissues. In this study, mutation levels were characterised in three commonly sampled tissues ‐ blood, urine, skeletal muscle ‐ and correlated with disease burden.

• Publisher: Nature Publishing Group UK,John Wiley and Sons Inc,Springer Nature
• Subject: Adult / Age Factors / Aged / Disease Progression / DNA Copy Number Variations / DNA Mutational Analysis / DNA, Mitochondrial - analysis / DNA, Mitochondrial - blood / DNA, Mitochondrial - urine / EMBO16 / Female / Genes, Mitochondrial / Humans / Linear Models / m.3243A>G / Male / MELAS / Middle Aged / mitochondrial disease / Mitochondrial Diseases - genetics / mtDNA copy number / mtDNA heteroplasmy / Muscle, Skeletal - metabolism / Mutation / Regression Analysis / Research Article / Sex Factors