Wallace D C, Lott M T, Shoffner J M, Ballinger S
Department of Genetics and Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia 30322.
Epilepsia. 1994;35 Suppl 1:S43-50. doi: 10.1111/j.1528-1157.1994.tb05928.x.
Recent discoveries in mitochondrial clinical genetics have revealed that a broad spectrum of clinical phenotypes are associated with mutations in mitochondrial DNA. Diseases caused by mutations in mitochondrial DNA are by nature quantitative. Myoclonic epilepsy and ragged-red fiber disease are caused by a mutation in the transfer RNA gene lysine. Although everyone in a maternal lineage will harbor the same mutation, the nature and severity of the symptoms vary markedly among individuals. This variability correlates with the inherited percentage of mutations in the individual's mitochondrial DNA and the individual's age. Age-related expression of mitochondrial disease has also been demonstrated for mitochondrial DNA deletions. Although deletions that retain both origins of replication result in late-onset disease because of the progressive enrichment of the deleted mitochondrial DNA, a 10.4-kb deletion that lacks the light-strand replication origin and maintains a stable mutant percentage in both tissues and cultured cells has been discovered. This deletion is associated with adult-onset diabetes and deafness, but not with ophthalmoplegia, ptosis, or mitochondrial myopathy. Biochemically, it causes a generalized defect in mitochondrial protein synthesis and oxidative phosphorylation. The age-related decline in oxidative phosphorylation could reflect the accumulation of somatic mitochondrial DNA mutations. Inhibition of oxidative phosphorylation stimulates this accumulation. The general paradigm for mitochondrial DNA diseases may be that inherited mutations inhibit the electron transport chain. This damages the mitochondrial DNA, further reducing oxidative phosphorylation. Ultimately, oxidative phosphorylation drops below the expression threshold of cells and tissues, and clinical symptoms appear.
线粒体临床遗传学的最新发现表明，广泛的临床表型与线粒体DNA突变有关。线粒体DNA突变引起的疾病本质上是定量的。肌阵挛性癫痫伴蓬毛样红纤维病由赖氨酸转运RNA基因突变引起。虽然母系血统中的每个人都会携带相同的突变，但症状的性质和严重程度在个体之间有明显差异。这种变异性与个体线粒体DNA中突变的遗传比例以及个体年龄相关。线粒体DNA缺失的年龄相关表达也已得到证实。虽然保留两个复制起点的缺失由于缺失的线粒体DNA的逐渐富集而导致迟发性疾病，但已发现一种10.4 kb的缺失，该缺失缺乏轻链复制起点，并在组织和培养细胞中保持稳定的突变比例。这种缺失与成人发病的糖尿病和耳聋有关，但与眼肌麻痹、上睑下垂或线粒体肌病无关。在生物化学方面，它导致线粒体蛋白质合成和氧化磷酸化的普遍缺陷。氧化磷酸化与年龄相关的下降可能反映了体细胞线粒体DNA突变的积累。氧化磷酸化的抑制会刺激这种积累。线粒体DNA疾病的一般模式可能是遗传突变抑制电子传递链。这会损害线粒体DNA，进一步降低氧化磷酸化。最终，氧化磷酸化降至细胞和组织的表达阈值以下，临床症状出现。
