Open Accessmt DNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease
Author(s) -
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 Gráinne S,
McNally Richard JQ,
Taylor Robert W,
Turnbull Doug M,
McFarland Robert
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708262
Subject(s) - heteroplasmy , mitochondrial dna , disease , mitochondrial disease , biology , genetics , burden of disease , medicine , gene
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 (mt DNA ) 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 mt DNA 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 mt DNA 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 mt DNA copy number may also influence disease severity.