Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis.
Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis.
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DOI：
10.1371/journal.pgen.1001352
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发表时间：
2011-03
期刊：
影响因子：
4.5
通讯作者：
Armanios M
中科院分区：
文献类型：
--
作者：
Alder JK;Cogan JD;Brown AF;Anderson CJ;Lawson WE;Lansdorp PM;Phillips JA 3rd;Loyd JE;Chen JJ;Armanios M
端粒酶逆转录酶通过从其积分RNA成分中的一个短模板复制来将新的端粒综合到染色体末端。在端粒合成过程中，端粒酶连续添加了多个短DNA重复，该属性称为重复加法。但是，尚不完全了解端粒长度维持的过程对端粒长度维持的后果。端粒酶中的种系突变会导致端粒缩短综合征的单倍不足，最常见于年龄相关的疾病特发性肺纤维化。我们确定了两个肺纤维化家族，它们在端粒酶逆转录酶基因HTERT的催化结构域中共享两个非同义取代：V791I和V867M。这两个变体落在同一HTERT等位基因上，并与端粒缩短有关。家谱表明，血统可以分享19世纪的一个祖先，遗传学研究证实，这两个家庭有一个共同的创始人。功能研究表明，尽管双突变体并未显着影响首次重复添加，但HTERT V791I-V867M在体外重复添加加工性添加性添加性均严重缺陷。我们的数据确定了具有新颖的功能丧失机制的端粒酶中的祖传突变。他们表明，端粒重复添加过程是端粒长度和端粒介导的疾病的关键决定因素。
基本端粒酶成分中的突变会导致短端粒介导的各种疾病。最常见的是，这些疾病在与年龄有关的疾病中表现出来：特发性肺纤维化。端粒酶使用专门的逆转录酶HTERT合成端粒重复序列，该酶从其内在RNA中的一个短模板中复制。为了添加较长的端粒界，端粒酶添加了一次重复，然后依次重复进行其他重复。该特性称为重复加工性，是端粒酶聚合酶独有的。我们确定了两个家庭，它们在HTERT的催化域中共享了两个独特的变体：V791I和V8.67M。这些变体共隔离，表明它们在同一个等位基因上，并且与端粒短相关。家族史表明，这两个家庭可能有一个祖先，遗传研究证实他们有一个共同的创始人。端粒酶的重构表明，尽管双重突变体并未显着影响端粒酶添加单个端粒重复的能力，但HTERT 791I-867M在重复添加过程中存在严重的缺陷。我们的数据确定了端粒酶中的祖先突变；该突变具有独特的功能丧失机制。端粒添加过程中的缺陷是端粒长度维持和与端粒相关疾病的重要决定因素。
The telomerase reverse transcriptase synthesizes new telomeres onto chromosome ends by copying from a short template within its integral RNA component. During telomere synthesis, telomerase adds multiple short DNA repeats successively, a property known as repeat addition processivity. However, the consequences of defects in processivity on telomere length maintenance are not fully known. Germline mutations in telomerase cause haploinsufficiency in syndromes of telomere shortening, which most commonly manifest in the age-related disease idiopathic pulmonary fibrosis. We identified two pulmonary fibrosis families that share two non-synonymous substitutions in the catalytic domain of the telomerase reverse transcriptase gene hTERT: V791I and V867M. The two variants fell on the same hTERT allele and were associated with telomere shortening. Genealogy suggested that the pedigrees shared a single ancestor from the nineteenth century, and genetic studies confirmed the two families had a common founder. Functional studies indicated that, although the double mutant did not dramatically affect first repeat addition, hTERT V791I-V867M showed severe defects in telomere repeat addition processivity in vitro. Our data identify an ancestral mutation in telomerase with a novel loss-of-function mechanism. They indicate that telomere repeat addition processivity is a critical determinant of telomere length and telomere-mediated disease. Mutations in the essential telomerase components cause a spectrum of diseases mediated by short telomeres. Most frequently, these disorders manifest in the lung in an age-related disease: idiopathic pulmonary fibrosis. Telomerase synthesizes telomere repeats using a specialized reverse transcriptase, hTERT, that copies from a short template within its intrinsic RNA. In order to add long telomere tracts, telomerase adds a single repeat followed by additional repeats successively. This property, known as repeat addition processivity, is unique to the telomerase polymerase. We identified two families that shared two unique variants in the catalytic domain of hTERT: V791I and V867M. The variants co-segregated, indicating they are on the same allele, and were associated with short telomeres. Family history suggested the two families may have a single ancestor, and genetic studies confirmed they had a common founder. Telomerase reconstitution indicated that, although the double mutant did not significantly affect telomerase's ability to add a single telomere repeat, hTERT 791I-867M had severe defects in repeat addition processivity. Our data identify an ancestral mutation in telomerase; this mutation possesses a unique loss-of-function mechanism. Defects in telomere addition processivity are important determinants of telomere length maintenance and of telomere-associated disease.
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影响因子：
14.9
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1164/rccm.200804-550oc
发表时间：
2008-10-01
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作者：
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