Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia
Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia
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DOI：
10.1056/nejmoa042980
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发表时间：
2005-04-07
影响因子：
158.5
通讯作者：
Young, NS
中科院分区：
文献类型：
--
作者：
Yamaguchi, H;Calado, RT;Young, NS
背景：端粒酶RNA组成基因TERC的突变，在先天性再生障碍性贫血和一些明显获得性造血功能衰竭的病例中导致端粒缩短。我们研究了端粒酶其他成分的基因突变是否也发生在再生障碍性贫血中。方法：我们从124例明显获得性再生障碍性贫血患者和282例对照者的血液或骨髓细胞中筛选TERT、DKC1、NHP2和NOP10基因的序列变异；另外对81名患者和246名对照者进行了TERT基因变异检测。端粒长度和外周血白细胞端粒酶活性评估患者携带遗传变异。将鉴定出的突变转染到端粒酶缺陷细胞系中，研究其对端粒酶功能的影响及其作用机制。结果：在7名不相关的患者中，端粒酶逆转录酶催化酶基因TERT中发现了5个杂合的非同义突变（导致相应蛋白质的氨基酸变化）。这些患者的白细胞端粒短，端粒酶活性低。在其中3例患者中，在颊粘膜细胞中也检测到这种突变。携带突变的家庭成员端粒短，端粒酶活性降低，但没有明显的血液异常。在端粒酶缺陷细胞系中，野生型TERT和TERT与再生障碍性贫血相关突变的共表达结果表明，TERT突变导致端粒缩短的机制是单倍功能不全。结论：TERT基因杂合突变通过单倍功能不全损害端粒酶活性，可能是骨髓衰竭的危险因素。
BACKGROUND:Mutations in TERC, the gene for the RNA component of telomerase, cause short telomeres in congenital aplastic anemia and in some cases of apparently acquired hematopoietic failure. We investigated whether mutations in genes for other components of telomerase also occur in aplastic anemia.METHODS:We screened blood or marrow cells from 124 patients with apparently acquired aplastic anemia and 282 control subjects for sequence variations in the TERT, DKC1, NHP2, and NOP10 genes; an additional 81 patients and 246 controls were examined for genetic variations in TERT. Telomere lengths and the telomerase activity of peripheral-blood leukocytes were evaluated in patients carrying genetic variants. Identified mutations were transfected into telomerase-deficient cell lines to examine their effects and their mechanism of action on telomerase function.RESULTS:Five heterozygous, nonsynonymous mutations (which cause an amino acid change in the corresponding protein) were identified in TERT, the gene for the telomerase reverse transcriptase catalytic enzyme, among seven unrelated patients. Leukocytes from these patients had short telomeres and low telomerase enzymatic activity. In three of these patients, the mutation was also detected in buccal mucosa cells. Family members carrying the mutations also had short telomeres and reduced telomerase activity but no evident hematologic abnormality. The results of coexpression of wild-type TERT and TERT with aplastic anemia-associated mutations in a telomerase-deficient cell line suggested that haploinsufficiency was the mechanism of telomere shortening due to TERT mutations.CONCLUSIONS:Heterozygous mutations in the TERT gene impair telomerase activity by haploinsufficiency and may be risk factors for marrow failure.