The myoclonic epilepsy and ragged-red fiber mutation provides new insights into human mitochondrial function and genetics
The myoclonic epilepsy and ragged-red fiber mutation provides new insights into human mitochondrial function and genetics
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DOI：
10.1086/301813
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发表时间：
1998-04-01
影响因子：
9.8
通讯作者：
Chomyn, A
中科院分区：
文献类型：
--
作者：
Chomyn, A
在迄今报道的导致人类疾病的约50个mtDNA点突变中，有35个发生在tRNA基因中（Schon等人，1997年）。其中，研究得最好的可能是tRNALys基因8344位的ArG转位，该突变可导致肌阵挛性癫痫和红纤维褴褛综合征（MERRF; Shoffner et al. 1990）。这种疾病是一种以肌阵挛性癫痫、共济失调和线粒体肌病为特征的脑肌病，在一些个体中，除了大脑和骨骼肌之外的组织还存在额外的功能障碍（Schon等，1997）。对一位MERRF患者的骨骼肌横切面进行组织学分析，用改良的Gomori三色染色法染色，发现存在“粗糙的红色纤维”，肌肉纤维周围呈斑点状，红色斑块代表线粒体在肌层下积聚。哺乳动物线粒体基因组包含13个阅读框，它们编码呼吸链酶复合物和h - atp酶的亚基（Anderson et al. 1981; Attardi et al. 1986）。mtDNA还包含大小rnas和22个tRNAs的基因。后者基因编码一套完整的trna，足以支持线粒体蛋白质的合成。每个线粒体tRNA基因都是翻译所必需的；也就是说，没有冗余，也没有tRNA被输入线粒体。像许多有害的tRNA突变一样，8344 tRNALys突变发生在异质状态：MERRF患者同时携带该基因的突变型和野生型等位基因。在一个MERRF母系中，突变DNA的比例在个体之间是不同的，甚至在同一个体的组织之间也是不同的（见Shoffner和Wallace 1992；也见Poulton 1998[在本期]）。先证者携带突变的亲属通常不受影响，或者他们可能只表现出轻微的症状，如听力
Of the∼ 50 mtDNA point mutations, reported so far, that cause disease in humans, x35 occur in tRNA genes (Schon et al. 1997). Of these, perhaps the best-studied is the ArG transition at position 8344 in the tRNALys gene, the mutation that causes myoclonic epilepsy and ragged-red fiber syndrome (MERRF; Shoffner et al. 1990). This disorder is an encephalomyopathy characterized by myoclonic epilepsy, ataxia, and mitochondrial myopathy, with additional dysfunction, in some individuals, in tissues other than brain and skeletal muscle (Schon et al. 1997). Histological analysis of transverse sections of a MERRF patient’s skeletal muscle, stained with Gomori’s modified trichrome stain, reveals the presence of “ragged red fibers,” muscle fibers that exhibit peripheral blotchy, red patches that represent subsarcolemmal accumulations of mitochondria. The mammalian mitochondrial genome contains 13 reading frames, which encode subunits of respiratorychain enzyme complexes and the H-ATPase (Anderson et al. 1981; Attardi et al. 1986). mtDNA also contains genes for the large and small rRNAs and for 22 tRNAs. The latter genes encode a complete set of tRNAs, sufficient to support mitochondrial protein synthesis. Each mitochondrial tRNA gene is essential for translation; that is, there is no redundancy, and no tRNA appears to be imported into mitochondria. The 8344 tRNALys mutation, like many deleterious tRNA mutations, occurs in a heteroplasmic state: a MERRF patient carries both the mutant and the wildtype alleles of the gene. The proportion of mutant DNA varies among individuals within a MERRF maternal lineage—and even among the tissues of the same individual (reviewed in Shoffner and Wallace 1992; see also Poulton 1998 [in this issue]). The relatives of the proband who carry the mutation are often unaffected, or they may exhibit only milder symptoms such as hearing