A mutation in the H/ACA box of telomerase RNA component gene (TERC) in a young patient with myelodysplastic syndrome.
A mutation in the H/ACA box of telomerase RNA component gene (TERC) in a young patient with myelodysplastic syndrome.
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DOI：
10.1186/1471-2350-15-68
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发表时间：
2014-06-19
影响因子：
--
通讯作者：
Young NS
中科院分区：
文献类型：
--
作者：
Ueda Y;Calado RT;Norberg A;Kajigaya S;Roos G;Hellstrom-Lindberg E;Young NS
端粒是位于真核生物染色体末端的重复序列（脊椎动物中的六核苷酸TTAGGG），保护DNA免于末端连接或降解。端粒在每个细胞周期中变得更短，但端粒酶，一种核糖核蛋白复合物，加剧了这种损耗。端粒酶RNA组分（TERC）是端粒酶的基本元件，充当端粒延伸的模板。TERC的H/ACA结构域是端粒生物发生所必需的。端粒酶组分的突变允许加速端粒丢失，导致各种疾病表现，包括骨髓衰竭。到目前为止，这是第一个详细报告TERC中与人类疾病相关的H盒突变。一名26岁的男性骨髓增生异常综合征（MDS）有非常短的端粒。测序鉴定出患者TERC基因的H盒中的单个杂合突变。同样的突变也存在于他的父亲和他的儿子，这表明它是种系起源。与年龄匹配的健康对照组相比，父亲血液中的端粒长度较短，而儿子和患者的精子细胞中的端粒长度正常。体外实验表明，该突变是负责端粒缩短在病人的白细胞，并有助于在我们的病人骨髓衰竭的发病机制。我们分析了TERC的H盒突变（A377 G）在一个年轻的MDS患者谁有显着短的年龄端粒。由于端粒保护染色体不稳定，因此这种遗传病变是患者血液学表现的原因，包括骨髓衰竭和造血干细胞室中的非整倍体，这是非常合理的。
Telomeres are repeated sequences (the hexanucleotide TTAGGG in vertebrates) located at chromosome ends of eukaryotes, protecting DNA from end joining or degradation. Telomeres become shorter with each cell cycle, but telomerase, a ribonucleoprotein complex, alleviates this attrition. The telomerase RNA component (TERC) is an essential element of telomerase, serving as a template for telomere elongation. The H/ACA domain of TERC is indispensable for telomere biogenesis. Mutations in the telomerase components allow accelerated telomere loss, resulting in various disease manifestations, including bone marrow failure. To date, this is the first detailed report of an H-box mutation in TERC that is related to human disease. A 26-year-old man with myelodysplastic syndrome (MDS) had very short telomeres. Sequencing identified a single heterozygous mutation in the H box of the patient’s TERC gene. The same mutation was also present in his father and his son, demonstrating that it was germline in origin. The telomere length in the father’s blood was shorter compared to age-matched healthy controls, while it was normal in the son and also in the sperm cells of the patient. In vitro experiments suggested that the mutation was responsible for the telomere shortening in the patient’s leukocytes and contributed to the pathogenesis of bone marrow failure in our patient. We analyzed a mutation (A377G) in the H box of TERC in a young MDS patient who had significantly short-for-age telomeres. As telomeres protect chromosomes from instability, it is highly plausible that this genetic lesion was responsible for the patient’s hematological manifestations, including marrow failure and aneuploidy in the hematopoietic stem cell compartment.
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影响因子：
4
作者：
Aston KI;Hunt SC;Susser E;Kimura M;Factor-Litvak P;Carrell D;Aviv A
通讯作者：
Aviv A
影响因子：
14.9
作者：
Cawthon RM
通讯作者：
Cawthon RM
DOI：
10.1073/pnas.0501724102
发表时间：
2005-11-08
影响因子：
11.1
作者：
Nordfjäll, K;Larefalk, Å;Roos, G
通讯作者：
Roos, G
影响因子：
168.9
作者：
Fogarty, PF;Yamaguchi, H;Young, NS
通讯作者：
Young, NS
影响因子：
5.2
作者：
Nordfjall, Katarina;Svenson, Ulrika;Roos, Goran
通讯作者：
Roos, Goran