Clinical and genetic heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase γ
Clinical and genetic heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase γ
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DOI：
10.1001/archneur.60.9.1279
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发表时间：
2003-09-01
影响因子：
--
通讯作者：
DiMauro, S
中科院分区：
文献类型：
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作者：
Filosto, M;Mancuso, M;DiMauro, S
背景：孟德尔形式的进行性外眼肌麻痹（PEO）与多个线粒体DNA缺失相关，是临床异质性疾病，以显性或隐性特征传播。常染色体显性PEO是由至少3个基因突变引起的：腺嘌呤核苷酸易位子-1 (ANT1)，编码肌肉特异性腺嘌呤核苷酸易位子染色体10开放阅读框2 (C10orf2)，编码闪烁解旋酶；和聚合酶（POLG），编码聚合酶的a亚基。POLG突变也可引起常染色体隐性PEO，这通常与多系统疾病有关。目的和方法：为了进一步研究POLG基因突变的频率和基因型-表型相关性，我们采用单链构象多态性分析和直接测序技术筛选了30例家族性或散发性PEO和肌肉多发线粒体DNA缺失但ANTI和C10orf2未发生突变的患者。结果：4例无亲缘关系的患者出现新的POLG突变。一名患有PEO和智力迟钝的妇女有一个杂合的Gly1076Val突变。两名患者，一名患有PEO、运动不耐受和胃肠运动障碍，另一名患有PEO、神经病变、耳聋和性腺功能减退，都有Pro587Leu改变。第4例患者为Ala889Thr和Arg579Trp突变复合杂合，患有PEO、胃肠运动障碍和神经病变。在120个健康对照等位基因中未检测到这些突变。结论：我们的研究结果表明，POLG突变占PEO和多线粒体DNA缺失患者的很大比例（13%），并导致临床和遗传异质性疾病。
Background: The mendelian forms of progressive external ophthalmoplegia (PEO) associated with multiple mitochondrial DNA deletions are clinically heterogeneous disorders transmitted as dominant or recessive traits. Autosomal dominant PEO is caused by mutations in at least 3 genes: adenine nucleotide translocator-1 (ANT1), encoding the muscle-specific adenine nucleotide translocator chromosome 10 open reading frame 2 (C10orf2), encoding Twinkle helicase; and polymerase gamma (POLG), encoding the a subunit of polymerase gamma. Mutations in POLG can also cause autosomal recessive PEO, which is often associated with multisystemic disorders.Objective and Methods: To further investigate the frequency and genotype-phenotype correlations of mutations in the POLG gene, we used single-stranded conformational polymorphism analysis and direct sequencing to screen 30 patients with familial or sporadic PEO and multiple mitochondrial DNA deletions in muscle but without mutations in ANTI and C10orf2.Results: Four unrelated patients had novel POLG mutations. A woman with PEO and mental retardation had a heterozygous Gly1076Val mutation. Two patients, one with PEO, exercise intolerance, and gastrointestinal dysmotility and the other with PEO, neuropathy, deafness, and hypogonadism, both had a Pro587Leu change. The fourth patient, who was compound heterozygous for Ala889Thr and Arg579Trp mutations, had PEO, gastrointestinal dysmotility, and neuropathy. These mutations were not detected in 120 healthy control alleles.Conclusions: Our results demonstrate that POLG mutations account for a substantial proportion of patients (13%) with PEO and multiple mitochondrial DNA deletions and cause both clinically and genetically heterogeneous disorders.