线粒体拷贝数变异在常见线粒体病表型差异中的作用

Mitochondrial disease is characterized by its genetic heterogeneity, and the relationship between genotype and phenotype is highly complicated. Recently, some researchers have reported that "mutation threshold" and mitochondrial copy number variation may cooperatively attribute to the clinical manifestations of mitochondrial disease. We attempt to further study the relationship between mitochondrial copy number and clinical diversity of mitochondrial disease on the basis of our previous findings that A3243G mutation ratio in urinary cells closely correlated with severity of the disease, and that mitochondrial copy number in urinary cells was higher in patients than in normal subjects. We will recruit 300 mitochondrial disease patients including mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS), myoclonic epilepsy with ragged-red fiber(MERRF) and Leigh syndrome(LS) to examine their mitochondrial copy number in blood and urinary cells, and then compare the copy number with normal controls,correlat the copy number with their phenotype, and observe changes of the copy number before and after treatment. This study may provide informations about impacts and mechanisms of the mutations, the pathogenesis of the disease, and the approaches to improve diagnosis, treatment, and prevention of the disease.

线粒体病是一组由于遗传缺陷引起线粒体ATP合成障碍而导致的一组复杂的异质性疾病，基因型与临床表型的关系复杂。近来认为 "突变阈值"效应和线粒体拷贝数变异可能共同决定线粒体病的临床表型。本课题即研究线粒体拷贝数变化与线粒体病临床表型的关系。前期发现在携带线粒体DNA A3243G突变患者的尿液中A3243G突变比例的高低与患者的发病年龄以及多种临床表现密切相关，且尿液细胞线粒体拷贝数增高。因此本课题组计划收集300例携带常见线粒体突变的线粒体病患者，包括携带A3243G、T8993G、 T8993C和 A8344G突变的患者，研究他们外周血和尿液中线粒体拷贝数与正常人线粒体拷贝数的差异；研究患者外周血和尿液线粒体拷贝数与各种临床表型的相关性，并研究患者治疗前后血液和尿液中线粒体拷贝数的变化。这将有助于明确突变的功能和作用机制，以及线粒体病的病理发生和线粒体疾病的诊断、预防和治疗。

线粒体病是一组由于遗传缺陷引起线粒体ATP合成障碍而导致的一组复杂的异质性疾病，基因型与临床表型的关系复杂，本课题主要研究线粒体拷贝数变化与线粒体病临床表型的关系。本课题收集300例携带常见线粒体突变的线粒体病患者，包括携带A3243G、T8993G、 T8993C和 A8344G突变的患者，研究他们外周血和尿液中线粒体拷贝数与正常人线粒体拷贝数的差异，并研究患者治疗前后血液和尿液中线粒体拷贝数的变化。研究发现： 线粒体基因组A3243G、A8344G和T8993C/G突变所致的线粒体病患者尿液野生型mtDNA拷贝数、突变比例与临床表型的复杂程度密切相关，野生型mtDNA拷贝数越低，突变比例越高临床表型越复杂；线粒体患者经鸡尾酒疗法治疗后，临床症状明显改善组治疗前后拷贝数上升明显，而“症状更差组”治疗前后拷贝数上升不明显。线粒体拷贝数变异为揭示线粒体疾病的临床表型差异奠定了基础。另外，课题还将线粒体基因组常见缺失（线粒体DNA4977bp缺失，ΔmtDNA4977）作为切入点，研究线粒体DNA4977bp缺失突变与线粒体基因病的临床表型的相关性。研究发现：线粒体DNA4977bp缺失呈现年龄依赖性；在线粒体病组，线粒体DNA4977bp 缺失明显高于正常对照组，提示∆mtDNA4977与无热点突变的线粒体病发病有关，mtDNA总拷贝数越低，突变比例越高，临床表型越复杂。这将有助于明确突变的功能和作用机制，以及线粒体病的病理发生和线粒体疾病的诊断、预防和治疗。

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