Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high.
Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high.
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发表时间：
1992-04
影响因子：
9.8
通讯作者：
Y. Tatuch;J. Christodoulou;A. Feigenbaum;J. Clarke;J. Wherret;C. Smith;N. Rudd;R. Petrova-Benedict;B. Robinson
中科院分区：
文献类型：
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作者：
Y. Tatuch;J. Christodoulou;A. Feigenbaum;J. Clarke;J. Wherret;C. Smith;N. Rudd;R. Petrova-Benedict;B. Robinson
一名表现为乳酸血症、低眼压和神经退行性疾病的女婴在7个月大时死亡。尸检发现了典型的Leigh病病变，既在基底节，也在脑干。一位姨妈和舅舅在经历了类似的临床病程后分别去世了1岁和5个月，而另一位叔叔，现在33岁，患有视网膜色素变性和共济失调，是智力低下。对先证者的mtDNA进行了限制性内切酶消化分析，发现8993位发生了T-G突变，产生了一个新的Avai限制酶切位点。ATP6基因中存在的突变导致精氨酸残基取代亮氨酸。根据激光密度测量法，标引患者的皮肤成纤维细胞、脑、肾和肝组织中有超过95%的mtDNA异常。一岁时去世的阿姨，她的淋巴母细胞中有超过95%的线粒体DNA异常。患有视网膜色素变性的叔叔的皮肤成纤维细胞和淋巴母细胞中分别有78%和79%的mtDNA异常，而一位无症状的阿姨和她的儿子没有这种突变的痕迹。指示病例的母亲在她的皮肤成纤维细胞和淋巴母细胞中分别有71%和39%的mtDNA异常，这表明在一个个体内，异质性可以在组织特异性的基础上是可变的。这表明，除了Holt等人描述的共济失调和视网膜色素变性的表型外，8993位的mtDNA突变还可以产生Leigh病的临床表型。
A female infant showing lacticacidemia, hypotonia, and neurodegenerative disease died at 7 mo of age. Autopsy revealed lesions typical of Leigh disease, both in the basal ganglia and in the brain stem. A maternal aunt and uncle died 1 year and 5 mo, respectively, after following a similar clinical course, while another uncle, presently 33 years of age, has retinitis pigmentosa and ataxia and is mentally retarded. PCR restriction-digest analysis of mtDNA isolated from the proband revealed a T-to-G change at position 8993, creating a new AvaI restriction site. The mutation present in the ATP 6 gene results in the substitution of an arginine residue for a leucine. The indexed patient had greater than 95% abnormal mtDNA in her skin fibroblasts, brain, kidney, and liver tissues, as measured by laser densitometry. The maternal aunt who died at age 1 year had greater than 95% abnormal mtDNA in her lymphoblasts. The uncle with retinitis pigmentosa had 78% and 79% abnormal mtDNA in his skin fibroblasts and lymphoblasts, respectively, while an asymptomatic maternal aunt and her son had no trace of this mutation. The mother of the index case had 71% and 39% abnormal mtDNA in her skin fibroblasts and lymphoblasts, respectively, showing that the heteroplasmy can be variable, on a tissue-specific basis, within one individual. This shows that mtDNA mutations at 8993 can produce the clinical phenotype of Leigh disease in addition to the phenotype of ataxia and retinitis pigmentosa described by Holt et al.(ABSTRACT TRUNCATED AT 250 WORDS)