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

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

Abstract 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 = ...

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Main Authors: John P Grady, Sarah J Pickett, Yi Shiau Ng, Charlotte L Alston, Emma L Blakely, Steven A Hardy, Catherine L Feeney, Alexandra A Bright, Andrew M Schaefer, Gráinne S Gorman, Richard JQ McNally, Robert W Taylor, Doug M Turnbull, Robert McFarland
Format: Article
Language:English
Published: Springer Nature 2018-05-01
Series:EMBO Molecular Medicine
Subjects:
m.3243A>G
MELAS
mitochondrial disease
mtDNA copy number
mtDNA heteroplasmy
Online Access:https://doi.org/10.15252/emmm.201708262
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Summary:Abstract 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 (R2 = 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 (R2 = 0.27, P < 0.001). In muscle, heteroplasmy, age and mtDNA copy number explain a higher proportion of variability in disease burden (R2 = 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.
ISSN:1757-4676
1757-4684

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