Constitutional telomerase mutations are genetic risk factors for cirrhosis.
Constitutional telomerase mutations are genetic risk factors for cirrhosis.
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体质端粒酶突变是肝硬化的遗传危险因素。
DOI：
10.1002/hep.24173
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发表时间：
2011-05
期刊：
影响因子：
13.5
通讯作者：
Young, Neal S.
中科院分区：
文献类型：
--
作者：
Calado, Rodrigo T.;Brudno, Jennifer;Mehta, Paulomi;Kovacs, Joseph J.;Wu, Colin;Zago, Marco A.;Chanock, Stephen J.;Boyer, Thomas D.;Young, Neal S.
一些肝病患者进展为肝硬化，但肝硬化发展的风险因素尚不清楚。先天性角化不良是一种遗传性骨髓衰竭综合征，与皮肤粘膜异常、肺纤维化和肝硬化有关，是由端粒酶复合体基因的生殖系突变引起的。我们研究了端粒酶突变是否也发生在散发性肝硬化。2008年5月至2009年7月，在亚利桑那大学肝脏研究所接受治疗的134例常见病因的肝硬化患者和528例健康受试者通过直接测序筛查了TERT和TERC基因的变异;另外1472例对照者检查了患者中观察到的最常见的遗传变异。用定量聚合酶链反应测定白细胞端粒长度。通过将含有突变的载体转染到端粒酶缺陷的细胞系中来评估遗传变化的功能效应，并在细胞裂解物中测量端粒酶活性。134例肝硬化患者中有9例（7%）携带TERT错义变异，导致累积携带频率显著高于对照组（P=0.0009）。1例为纯合子，8例为杂合子。最常见的错义TERT变异体的等位基因频率在阿尔茨海默病患者中（2.6%）显著高于2000名对照（0.7%; P=0.0011）。另外一名患者携带TERC突变。包括6例突变病例在内的白血病患者的白细胞平均端粒长度短于年龄匹配的对照组（P=0.0004）。大多数TERT基因变体在体外降低端粒酶酶活性。与短端粒相关的端粒酶基因功能缺失变异是散发性肝硬化的危险因素
Some patients with liver disease progress to cirrhosis, but the risk factors for cirrhosis development are unknown. Dyskeratosis congenita, an inherited bone marrow failure syndrome associated with mucocutaneous anomalies, pulmonary fibrosis, andcirrhosis, is caused by germ-line mutations of genesin the telomerase complex. We examined whether telomerase mutations also occurred in sporadic cirrhosis. One hundred thirty-four patients with cirrhosis of common etiologies treated at the Liver Research Institute, University of Arizona, between May 2008 and July 2009, and 528healthy subjects were screened for variation in the TERT and TERC genes by direct sequencing; an additional 1472 controls were examined for the most common genetic variation observed in patients. Telomere length of leukocytes was measured by quantitative polymerase chain reaction. Functional effects of genetic changes were assessed by transfection of mutation-containing vectors into telomerase-deficient cell lines, and telomerase activity was measured in cell lysates. Nine of the 134 patients with cirrhosis (7%) carried a missense variant in TERT, resulting in a cumulative carrier frequency significantly higher than in controls (P=0.0009). One patient was homozygous and eight were heterozygous. The allele frequency for the most common missense TERT variant was significantly higher in cirrhotic patients (2.6%) than in 2000 controls (0.7%; P=0.0011). One additional patient carried a TERC mutation. The mean telomere length of leukocytesin cirrhotic patients, including six mutant cases, was shorter than in age-matched controls(P=0.0004). Most TERT gene variants reduced telomerase enzymatic activity in vitro. Loss-of-function telomerase gene variants associated with short telomeres are risk factors for sporadic cirrhosis.
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影响因子：
168.9
作者：
Fogarty, PF;Yamaguchi, H;Young, NS
通讯作者：
Young, NS
影响因子：
29.4
作者：
Huang, Hongjin;Shiffman, Mitchell L.;Wright, Teresa L.
通讯作者：
Wright, Teresa L.
影响因子：
56.9
作者：
Lingner, J;Hughes, TR;Cech, TR
通讯作者：
Cech, TR
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：
13.5
作者：
Hellier, S;Frodsham, AJ;Hill, AVS
通讯作者：
Hill, AVS