Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma
Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma
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DOI：
10.1093/humrep/del076
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发表时间：
2006-10-01
影响因子：
6.1
通讯作者：
Rahman, Shamima
中科院分区：
文献类型：
--
作者：
Pagnamenta, Alistair T.;Taanman, Jan-Willem;Rahman, Shamima
背景：卵巢早衰 (POF) 导致 40 岁之前绝经。最近，线粒体 DNA 聚合酶 γ (POLG) 催化亚基的突变被证明与进行性外眼肌麻痹 (PEO) 和线粒体 DNA (mtDNA) 多次大规模重排的家族中的 POF 分离。方法和结果：描述了一名患者、母亲和外祖母，均患有 POF 和 PEO。母亲在六十岁的时候患上了帕金森症。正常的线粒体DNA序列排除了线粒体遗传。聚合酶 γ 的序列分析揭示了与疾病分离的显性 Y955C 突变。 Southern 印迹分析表明成纤维细胞中 mtDNA 缺失（对照组为 43%）。相比之下，在骨骼肌中观察到线粒体 DNA 的多重重排，这与与其他呼吸链酶相比核编码复合物 II 活性相对较少的情况一致。天然凝胶的免疫印迹显示 DNA 聚合酶 γ 稳定性未受影响，而逆转录酶引物延伸测定表明成纤维细胞中聚合酶活性有降低的趋势。结论：本研究证实 POLG 突变可与 POF 和帕金森病分离，并首次证明 Y955C 突变可导致 mtDNA 耗竭。未来的筛查项目将确定 POLG 参与 POF 病因学的频率及其对生殖咨询的影响。
BACKGROUND: Premature ovarian failure (POF) results in menopause before the age of 40. Recently, mutations in the catalytic subunit of mitochondrial DNA polymerase gamma (POLG) were shown to segregate with POF in families with progressive external ophthalmoplegia (PEO) and multiple large-scale rearrangements of mitochondrial DNA (mtDNA). METHODS AND RESULTS: A patient, mother and maternal grandmother are described, all presenting with POF and PEO. The mother developed parkinsonism in her sixth decade. Normal mtDNA sequence excluded mitochondrial inheritance. Sequence analysis of polymerase gamma revealed a dominant Y955C mutation that segregated with disease. Southern blot analysis demonstrated mtDNA depletion in fibroblasts (43% of controls). In contrast, multiple rearrangements of mtDNA were seen in skeletal muscle, consistent with the relative sparing of nuclear-encoded complex II activity compared with other respiratory chain enzymes. Immunoblotting of native gels showed that DNA polymerase gamma stability was not affected, whereas a reverse-transcriptase primer-extension assay suggested a trend towards reduced polymerase activity in fibroblasts. CONCLUSIONS: This study confirms that POLG mutations can segregate with POF and parkinsonism and demonstrates for the first time that the Y955C mutation can lead to mtDNA depletion. Future screening projects will determine the frequency with which POLG is involved in the aetiology of POF and its impact on reproductive counselling.