Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations.
Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations.
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DOI：
10.1371/journal.pone.0010680
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发表时间：
2010-05-19
期刊：
影响因子：
3.7
通讯作者：
Garcia CK
中科院分区：
文献类型：
--
作者：
Diaz de Leon A;Cronkhite JT;Katzenstein AL;Godwin JD;Raghu G;Glazer CS;Rosenblatt RL;Girod CE;Garrity ER;Xing C;Garcia CK
端粒酶是一种催化核苷酸在染色体末端添加的酶。在特发性肺纤维化（IPF）患者中，编码端粒酶蛋白组分（TERT）的基因发生了罕见的功能缺失突变。在此，我们研究了杂合性TERT突变的多发性激酶中端粒长度和肺纤维化表型。我们从21个无关的家庭中鉴定出134个杂合性TERT突变个体。回顾性评价了现有的医疗记录、手术肺活检和X线片。从循环白细胞中分离的基因组DNA已被用于通过定量PCR测定来测量端粒长度。我们发现，端粒长度的TERT突变携带者的年龄依赖性的方式减少，并表现出逐步缩短与连续几代的突变遗传。没有TERT突变的家族成员的平均端粒长度比正常的短，这表明在没有遗传性TERT突变的情况下缩短的端粒长度的表观遗传。肺纤维化是一种年龄依赖性表型，在40岁以下的突变携带者中未见，但在60%的60岁或以上男性中发现;其发展与环境暴露（包括吸烟）相关。在74%的病例中观察到与IPF诊断一致的普通型间质性肺炎（UIP）的影像学CT模式，在86%的手术肺活检中观察到UIP的病理模式。与TERT突变相关的肺纤维化是进行性和致命的，诊断后平均生存期为3年。总体而言，TERT突变携带者表现出预期寿命缩短，男性和女性的平均死亡年龄分别为58岁和67岁。肺纤维化的一个亚类，如先天性角化不良、骨髓衰竭和肝病，代表了由端粒酶生殖细胞突变引起的"端粒病"，其特征是端粒长度短。未遗传TERT突变的家族成员的端粒长度比对照组短，表明缩短的亲本端粒长度设定点的表观遗传。
Telomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations. We have identified 134 individuals with heterozygous TERT mutations from 21 unrelated families. Available medical records, surgical lung biopsies and radiographs were evaluated retrospectively. Genomic DNA isolated from circulating leukocytes has been used to measure telomere lengths with a quantitative PCR assay. We find that telomere lengths of TERT mutation carriers decrease in an age-dependent manner and show progressive shortening with successive generations of mutation inheritance. Family members without TERT mutations have a shorter mean telomere length than normal, demonstrating epigenetic inheritance of shortened telomere lengths in the absence of an inherited TERT mutation. Pulmonary fibrosis is an age-dependent phenotype not seen in mutation carriers less than 40 years of age but found in 60% of men 60 years or older; its development is associated with environmental exposures including cigarette smoking. A radiographic CT pattern of usual interstitial pneumonia (UIP), which is consistent with a diagnosis of IPF, is seen in 74% of cases and a pathologic pattern of UIP is seen in 86% of surgical lung biopsies. Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis. Overall, TERT mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively. A subset of pulmonary fibrosis, like dyskeratosis congenita, bone marrow failure, and liver disease, represents a “telomeropathy” caused by germline mutations in telomerase and characterized by short telomere lengths. Family members within kindreds who do not inherit the TERT mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point.
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影响因子：
14.9
作者：
Cawthon RM
通讯作者：
Cawthon RM
DOI：
10.1073/pnas.0702703104
发表时间：
2007-07-17
影响因子：
11.1
作者：
Njajou, Omer T.;Cawthon, Richard M.;Hsueh, Wen-Chi
通讯作者：
Hsueh, Wen-Chi
影响因子：
56.9
作者：
FENG, JL;FUNK, WD;VILLEPONTEAU, B
通讯作者：
VILLEPONTEAU, B
DOI：
10.1164/rccm.200804-550oc
发表时间：
2008-10-01
影响因子：
24.7
作者：
Cronkhite, Jennifer T.;Xing, Chao;Garcia, Christine Kim
通讯作者：
Garcia, Christine Kim
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