Identification and functional characterization of novel telomerase variant alleles in Japanese patients with bone-marrow failure syndromes
Identification and functional characterization of novel telomerase variant alleles in Japanese patients with bone-marrow failure syndromes
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DOI：
10.1016/j.bcmd.2007.08.002
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发表时间：
2008-03-01
影响因子：
2.3
通讯作者：
Dan, Kazuo
中科院分区：
文献类型：
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作者：
Takeuchi, Junko;Ly, Hinh;Dan, Kazuo
由于东亚骨髓衰竭综合征 (BMFS) 的发病率比西方高 2-3 倍，我们检查了 100 名日本患者的外周血或骨髓细胞，以了解最近与疾病发病机制有关的端粒合成酶端粒酶的两个主要成分（hTERC RNA 和 hTERT 蛋白）是否可能存在致病性突变。我们分析了从 34 名获得性再生障碍性贫血 (AA) 患者、66 名骨髓增生异常综合征 (MDS) 患者和 120 名健康对照者收集的样本。除了在患者和健康个体中发现的 hTERC 启动子区域中的两个多态性种系序列变化（n-771A/G 和 n-714C 插入）和 11 个 hTERT 多态性之外，我们仅在 MDS 患者的 hTERC RNA 中发现了一种新的种系 C323T 突变。这种杂合的 C323T 突变消除了端粒酶活性，并以单倍体不足的方式发挥作用，调节细胞中的端粒酶活性。总之，本研究报告了一种新的端粒酶天然变体，它消除了端粒酶功能，可能导致 BMFS 患者端粒缩短和骨髓细胞减少。这项研究还强调了日本 BMFS 患者基因改变的罕见性，这表明其他因素可能在东亚的疾病发病机制中发挥着更重要的作用。 (c) 2007 Elsevier Inc. 保留所有权利。
As the incidence of bone-marrow failure syndromes (BMFS) is 2-3x higher in East Asia than in the West, we examined peripheral blood or marrow cells of 100 Japanese patients for possible pathogenic mutations in the two main components of the telomere-synthesizing enzyme telomerase (hTERC RNA and hTERT protein) that have recently been implicated in the disease pathogenesis. We analyzed samples collected from 34 patients with acquired aplastic anemia (AA), 66 patients with myelodysplastic syndromes (MDS) and 120 healthy controls. In addition to two polymorphic germ-line sequence changes (n-771A/G and n-714 C insertion) in the promoter region of hTERC and eleven hTERT polymorphisms that were identified in both patients and healthy individuals, we found a novel germ-line C323T mutation in the hTERC RNA in an MDS patient only. This heterozygous C323T mutation abolished telomerase enzymatic activity and functioned in a haploinsufficiency manner to modulate telomerase activity in cells. In summary, this study reports a novel telomerase natural variant that abolishes telomerase function, which may lead to telomere shortening and marrow hypocellularity in patients with BMFS. This study also highlights the rarity of genetic alterations in BMFS patients in Japan, which suggests that other factors may play a more prominent role in the disease pathogenesis in East Asia. (c) 2007 Elsevier Inc. All rights reserved.