Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema.
Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema.
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DOI：
10.1126/scitranslmed.aaf7837
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发表时间：
2016-08-10
影响因子：
17.1
通讯作者：
Armanios M
中科院分区：
文献类型：
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作者：
Stanley SE;Gable DL;Wagner CL;Carlile TM;Hanumanthu VS;Podlevsky JD;Khalil SE;DeZern AE;Rojas-Duran MF;Applegate CD;Alder JK;Parry EM;Gilbert WV;Armanios M
慢性阻塞性肺病和肺纤维化已被假设为代表过早衰老的表型。有时，它们聚集在家庭中，但其遗传基础尚不清楚。我们在肺纤维化-肺气肿患者中发现了核组装因子 1（NAF1）基因中罕见的移码突变，NAF1 是一种盒式 H/ACA RNA 生物合成因子。这些突变因端粒长度短、端粒酶 RNA 水平低以及肺外表现（包括骨髓增生异常综合征和肝脏疾病）而分离。在源自患者的细胞中检测到截短的 NAF1，并且在通过基因组编辑引入移码突变的细胞中，端粒酶 RNA 水平降低。突变体 NAF1 缺乏保守的羧基末端基序，我们证明这是核定位所必需的。为了了解疾病机制，我们使用 CRISPR（成簇规则间隔短回文重复序列）/Cas9（CRISPR 相关蛋白 9 核酸酶）生成 Naf1+/- 小鼠，发现它们的端粒酶 RNA 水平只有一半。其他盒 H/ACA RNA 水平也下降，但由 snoRNA 引导的 rRNA 假尿苷化完好无损。此外，第一代 Naf1+/- 小鼠没有表现出核糖体病理学的证据。我们的数据表明 NAF1 突变携带者的疾病是端粒介导的；他们表明，NAF1 单倍体不足通过降低端粒酶 RNA 的水平，同时避免 rRNA 假尿苷化，选择性地扰乱端粒长度稳态。端粒是防止染色体末端散开的保护帽。端粒酶（一种形成端粒的酶）的蛋白质或 RNA 成分携带突变的人，端粒较短，并且患有严重且往往致命的肺部疾病——肺纤维化。现在，斯坦利等人。在几名患者中发现其他突变，特别是那些干扰 RNA 生物发生的突变，也可能导致端粒短和肺部疾病。这项工作扩展了我们对端粒如何维持及其在人类疾病中的作用的理解。
Chronic obstructive pulmonary disease and pulmonary fibrosis have been hypothesized to represent premature aging phenotypes. At times, they cluster in families, but the genetic basis is not understood. We identified rare, frameshift mutations in the gene for nuclear assembly factor 1, NAF1, a box H/ACA RNA biogenesis factor, in pulmonary fibrosis–emphysema patients. The mutations segregated with short telomere length, low telomerase RNA levels, and extrapulmonary manifestations including myelodysplastic syndrome and liver disease. A truncated NAF1 was detected in cells derived from patients, and, in cells in which the frameshift mutation was introduced by genome editing, telomerase RNA levels were reduced. The mutant NAF1 lacked a conserved carboxyl-terminal motif, which we show is required for nuclear localization. To understand the disease mechanism, we used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein-9 nuclease) to generate Naf1+/− mice and found that they had half the levels of telomerase RNA. Other box H/ACA RNA levels were also decreased, but rRNA pseudouridylation, which is guided by snoRNAs, was intact. Moreover, first-generation Naf1+/− mice showed no evidence of ribosomal pathology. Our data indicate that disease in NAF1 mutation carriers is telomere-mediated; they show that NAF1 haploinsufficiency selectively disturbs telomere length homeostasis by decreasing the levels of telomerase RNA while sparing rRNA pseudouridylation. Telomeres are the protective caps that prevent the ends of chromosomes from unraveling. People carrying mutations in the protein or RNA component of telomerase, the enzyme that makes telomeres have short telomeres and a serious and often fatal lung disease– –pulmonary fibrosis. Now, Stanley et al. find in several patients that other mutations, specifically those that interfere with RNA biogenesis, can also cause both short telomeres and lung disease. This work expands our understanding of how telomeres are maintained and their role in human disease.