Telomere shortening in familial and sporadic pulmonary fibrosis
Telomere shortening in familial and sporadic pulmonary fibrosis
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DOI：
10.1164/rccm.200804-550oc
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发表时间：
2008-10-01
影响因子：
24.7
通讯作者：
Garcia, Christine Kim
中科院分区：
文献类型：
--
作者：
Cronkhite, Jennifer T.;Xing, Chao;Garcia, Christine Kim
理论基础：在特发性间质性肺炎的家族性和散发性病例中，已经发现端粒酶基因编码区的杂合性突变，TERT和TERC。目的：为了验证端粒缩短是否是肺纤维化的常见机制，我们对没有TERT或TERC编码突变的家族性或散发性疾病患者的端粒长度进行了表征。方法：采用改良的Southern印迹法、端粒酶限制性片段长度法和定量聚合酶链式反应方法，从正常对照组和肺纤维化患者的循环白细胞中提取基因组DNA，测量端粒长度。测量和主要结果：所有端粒酶突变的患者，包括新报道的TERT杂合子患者，端粒长度都较短。家族性肺纤维化先证者(24%)和未发现TERT或TERC编码突变的散发性病例(23%)端粒长度小于10百分位数的比例显著高于对照组(P=2.6×10(-8))。肺纤维化感染状态与端粒酶限制片段长度显著相关，即使在控制了年龄、性别和种族后也是如此(P=6.1×10(-11))。总体而言，25%的散发性肺纤维化患者和37%的家族性肺纤维化患者的端粒长度低于10%。结论：相当一部分肺纤维化患者的端粒长度较短，这不能用端粒酶编码突变来解释。循环中的白细胞端粒缩短可能是发生这种年龄相关性疾病的易感性增加的一个标志。
Rationale: Heterozygous mutations in the coding regions of the telomerase genes, TERT and TERC, have been found in familial and sporadic cases of idiopathic interstitial pneumonia. All affected patients with mutations have short telomeres.Objectives: To test whether telomere shortening is a frequent mechanism underlying pulmonary fibrosis, we have characterized telomere lengths in subjects with familial or sporadic disease who do not have coding mutations in TERT or TERC.Methods: Using a modified Southern blot assay, the telomerase restriction fragment length method, and a quantitative polymerase chain reaction assay we have measured telomere lengths of genomic DNA isolated from circulating leukocytes from normal control subjects and subjects with pulmonary fibrosis.Measurements and Main Results: All affected patients with telomerase mutations, including case subjects heterozygous for newly reported mutations in TERT, have short telomere lengths. A significantly higher proportion of probands with familial pulmonary fibrosis (24%) and sporadic case subjects (23%) in which no coding mutation in TERT or TERC was found had telomere lengths less than the 10th percentile when compared with control subjects (P = 2.6 X 10(-8)). Pulmonary fibrosis affectation status was significantly associated with telomerase restriction fragment lengths, even after controlling for age, sex, and ethnicity (P = 6.1 X 10(-11)). Overall, 25% of sporadic cases and 37% of familial cases of pulmonary fibrosis had telomere lengths less than the 10th percentile.Conclusions: A significant fraction of individuals with pulmonary fibrosis have short telomere lengths that cannot be explained by coding mutations in telomerase. Telomere shortening of circulating leukocytes may be a marker for an increased predisposition toward the development of this age-associated disease.