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JCI & CHEST J:端粒突变更易患肺部疾病

  1. 个体
  2. 染色体
  3. 生物钟
  4. 癌症
  5. 端粒突变
  6. 肺部疾病

来源:生物谷 2015-02-09 10:04

近日,刊登在国际杂志Journal of Clinical Investigation及CHEST Journal上的两篇研究论文中,来自杨百翰大学的研究者表示,他们知道我们中的大部分人什么时候死亡?但研究者并不不清楚我们确切的死亡事件,当然他们得出这样的结论得益于对我们机体染色体生物钟的研究,染色体末端的端粒可以帮助预测机体的寿命,其越短就表示我们寿命越短。

2015年2月9日 讯 /生物谷BIOON/ --近日,刊登在国际杂志Journal of Clinical InvestigationCHEST Journal上的两篇研究论文中,来自杨百翰大学的研究者表示,他们知道我们中的大部分人什么时候死亡?但研究者并不不清楚我们确切的死亡事件,当然他们得出这样的结论得益于对我们机体染色体生物钟的研究,染色体末端的端粒可以帮助预测机体的寿命,其越短就表示我们寿命越短。

较短的端粒可以帮助预测骨髓衰竭、肝脏疾病、皮肤及肺部疾病等;研究者在过去30年里一直从事端粒的相关研究,他们试图利用方法来延伸端粒,并且研究端粒的相关突变,而如今研究者发现了端粒和肺部疾病的关联。Alder教授说道,当我们出生时,我们的端粒非常长,随着年龄增长端粒会不断变短,本文中我们发现肺部疾病的个体端粒往往相比正常个体的端粒较短。

端粒是染色体的保护性帽子,就好象是鞋带儿上的塑料帽一样保护鞋带,当细胞分裂复制一次,端粒末端的DNA就会减少,因此在人的一生中随着细胞不断分裂,染色体末端的端粒就会不断变短。当端粒耗尽细胞就会失活或者死亡,从而引发疾病。某些科学家发现了可以延长端粒的方法,但这并不总是好的,因为维持长度的端粒往往也会引发并发症,比如癌症等疾病。

文章中,研究者发现,发生肺气肿的部分患者机体中在维持端粒的基因上往往会发生一些突变;如果已知端粒基因突变会引发肺纤维化,那么本文的研究就可以将端粒和肺部疾病相关联起来。端粒突变的家族会将这些遗传突变遗传给厚道,这就会导致后代也会携带较短的端粒,而携带较短端粒的个体或患肺部疾病的风险较高。

最后,研究者Mary Armanios指出,大部分人并不会意识到肺部疾病是引发美国人死亡的常见三大原因,而对端粒的研究或许对于预防肺部疾病也具有一定的指示意义;我们都知道吸烟者往往患肺部疾病的风险较高,本文研究或许也可推理出,吸烟的端粒突变个体往往患肺部疾病的风险或更高。(生物谷Bioon.com)

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Telomerase mutations in smokers with severe emphysema

Susan E. Stanley1,2, Julian J.L. Chen3, Joshua D. Podlevsky3, Jonathan K. Alder1, Nadia N. Hansel4, Rasika A. Mathias4, Xiaodong Qi3, Nicholas M. Rafaels4, Robert A. Wise4, Edwin K. Silverman5, Kathleen C. Barnes4,6 and Mary Armanios1,6

Mutations in the essential telomerase genes TERT and TR cause familial pulmonary fibrosis; however, in telomerase-null mice, short telomeres predispose to emphysema after chronic cigarette smoke exposure. Here, we tested whether telomerase mutations are a risk factor for human emphysema by examining their frequency in smokers with chronic obstructive pulmonary disease (COPD). Across two independent cohorts, we found 3 of 292 severe COPD cases carried deleterious mutations in TERT (1%). This prevalence is comparable to the frequency of alpha-1 antitrypsin deficiency documented in this population. The TERT mutations compromised telomerase catalytic activity, and mutation carriers had short telomeres. Telomerase mutation carriers with emphysema were predominantly female and had an increased incidence of pneumothorax. In families, emphysema showed an autosomal dominant inheritance pattern, along with pulmonary fibrosis and other telomere syndrome features, but manifested only in smokers. Our findings identify germline mutations in telomerase as a Mendelian risk factor for COPD susceptibility that clusters in autosomal dominant families with telomere-mediated disease including pulmonary fibrosis.

Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis

Jonathan K. Alder; Susan E. Stanley; Christa L. Wagner; Makenzie Hamilton; Vidya Sagar Hanumanthu; Mary Armanios

Short telomeres are a common defect in idiopathic pulmonary fibrosis, yet mutations in the telomerase genes account for only a subset of these cases. We identified a family with pulmonary fibrosis, idiopathic infertility and short telomeres. Exome sequencing of blood-derived DNA revealed two mutations in the telomere binding protein TINF2. The first was a 15 base pair deletion encompassing the exon 6 splice acceptor site, and the second was a missense mutation, Thr284Arg. Haplotype analysis indicated both variants fell on the same allele. However, lung-derived DNA showed predominantly the Thr284Arg allele indicating the deletion seen in the blood was acquired and may have a protective advantage since it diminished expression of the missense mutation. This mosaicism may represent functional reversion in telomere syndromes similar to what has been described for Fanconi anemia. No mutations were identified in over forty uncharacterized pulmonary fibrosis probands suggesting mutant TINF2 accounts for a small subset of familial cases. However, similar to affected individuals in this family, we identified a history of male and female infertility preceding the onset of pulmonary fibrosis in 11% of telomerase mutation carriers with TERT and TR mutations (5 of 45). Our findings identify TINF2 as a mutant telomere gene in familial pulmonary fibrosis, and suggest infertility may precede the presentation of pulmonary fibrosis in a small subset of adults with telomere syndromes.

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