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.
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DOI：
10.15252/emmm.201708262
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发表时间：
2018-06
影响因子：
11.1
通讯作者：
McFarland R
中科院分区：
文献类型：
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作者：
Grady JP;Pickett SJ;Ng YS;Alston CL;Blakely EL;Hardy SA;Feeney CL;Bright AA;Schaefer AM;Gorman GS;McNally RJ;Taylor RW;Turnbull DM;McFarland R
与致病性m.3243A>G变异相关的线粒体疾病是一种常见的、临床异质性的神经遗传性疾病。使用多元线性回归和线性混合模型，我们评估了通常测定的组织（血液N = 231，尿液N = 235，骨骼肌N = 77）代表与疾病负担和进展最强相关的m.3243A>G突变负荷和线粒体DNA（mtDNA）拷贝数。m.3243A>G水平在血液、肌肉和尿液中相关（R 2 = 0.61-0.73）。血液异质性下降约2.3%/年;我们已经扩展了以前发表的方法，以调整年龄。在尿液中，男性的mtDNA拷贝数较高，m.3243A>G突变负荷高出约20%;我们提出了调整这一点的公式。血液是携带m.3243A>G的个体中疾病负担和进展的最高度相关的突变测量;年龄增加和异质性贡献（R2 = 0.27，P < 0.001）。在肌肉中，异质性、年龄和mtDNA拷贝数解释了较高比例的疾病负担变异性（R2 = 0.40，P < 0.001），尽管活动水平和疾病严重程度可能影响拷贝数。虽然我们的数据表明年龄校正的血液m.3243A>G异质性是常规临床评估最方便和可靠的指标，但其他因素如mtDNA拷贝数也可能影响疾病的严重程度。
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.