Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus.
Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus.
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DOI：
10.1111/acel.12139
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发表时间：
2013-12
期刊：
影响因子：
7.8
通讯作者：
Chang S
中科院分区：
文献类型：
--
作者：
Gu P;Chang S
Coats plus是一种罕见的隐性疾病，以颅内钙化、血液异常和视网膜血管缺陷为特征。这种疾病是由CTC1突变引起的，CTC1是CTC1 - stn1 - ten1 （CST）复合体的成员，对端粒复制至关重要。端粒是维持基因组稳定所必需的特殊DNA/蛋白质结构。一些Coats plus患者显示端粒严重缩短，表明端粒功能障碍在疾病发病机制中起重要作用。这些患者以复合杂合方式遗传CTC1突变，其中一个等位基因编码移码突变，另一个等位基因编码错义突变。这些突变如何影响端粒功能尚不清楚。我们在这里报告了人类CTC1突变的第一个生化表征。我们发现所有CTC1移码突变都会产生截短或不稳定的蛋白产物，这些蛋白产物都不能与端粒上的STN1-TEN1形成复合体，导致端粒逐渐缩短并形成融合染色体。错义突变能够在端粒上形成CST复合物，但它们的表达水平通常被移码突变体抑制。我们的研究结果还首次证明，CTC1突变通过降低STN1的稳定性来降低其与DNA Polα相互作用的能力，从而促进端粒功能障碍，从而突出了以前未知的诱导端粒功能障碍的机制。
Coats plus is a rare recessive disorder characterized by intracranial calcifications, hematological abnormalities, and retinal vascular defects. This disease results from mutations in CTC1, a member of the CTC1–STN1–TEN1 (CST) complex critical for telomere replication. Telomeres are specialized DNA/protein structures essential for the maintenance of genome stability. Several patients with Coats plus display critically shortened telomeres, suggesting that telomere dysfunction plays an important role in disease pathogenesis. These patients inherit CTC1 mutations in a compound heterozygous manner, with one allele encoding a frameshift mutant and the other a missense mutant. How these mutations impact upon telomere function is unknown. We report here the first biochemical characterization of human CTC1 mutations. We found that all CTC1 frameshift mutations generated truncated or unstable protein products, none of which were able to form a complex with STN1–TEN1 on telomeres, resulting in progressive telomere shortening and formation of fused chromosomes. Missense mutations are able to form the CST complex at telomeres, but their expression levels are often repressed by the frameshift mutants. Our results also demonstrate for the first time that CTC1 mutations promote telomere dysfunction by decreasing the stability of STN1 to reduce its ability to interact with DNA Polα, thus highlighting a previously unknown mechanism to induce telomere dysfunction.
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影响因子：
64.8
作者：
Chen, Liuh-Yow;Redon, Sophie;Lingner, Joachim
通讯作者：
Lingner, Joachim
影响因子：
44.1
作者：
Huang, Chenhui;Dai, Xueyu;Chai, Weihang
通讯作者：
Chai, Weihang
影响因子：
5.7
作者：
Mason, Mark;Wanat, Jennifer J.;Skordalakes, Emmanuel
通讯作者：
Skordalakes, Emmanuel
DOI：
10.1056/nejmra0903373
发表时间：
2009-12-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Calado RT;Young NS
通讯作者：
Young NS
影响因子：
5.3
作者：
Nakamura, M;Nabetani, A;Ishikawa, F
通讯作者：
Ishikawa, F