期刊
HAEMATOLOGICA
卷 92, 期 8, 页码 1013-1020出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.11407
关键词
aplastic anemia; de novo; dyskeratosis congenita; haplo-insufficiency; telomerase; TERC
类别
资金
- Wellcome Trust
- MRC
Background and Objectives Functional characterization of heterozygous TERC (telomerase RNA component) and TERT (telomerase reverse transcriptase) mutations found in autosomal dominant dyskeratosis congenita (DC) and aplastic anemia (AA) shows that telomerase function is defective and that this is associated with short telomeres. This leads to reduced cell longevity with maximal impact on tissues with high proliferate potential. The aim of this study was to establish the role of TERC in the pathophysiology of uncharacterized patients with AA with some features of DC. Design and Methods The TERC gene was screened for mutations by denaturing high performance liquid chromatography. To determine the functional significance of TERC mutations telomerase activity was assessed in an in vitro (TRAP) assay and telomere length of patients' samples was determined using Southern blot analysis. Results This study led to the identification of four novel TERC mutations (G178A, C180T, Delta 52-86 and G2C) and a recurrent TERC mutation (Delta 110-113GACT). Interpretation and Conclusions Two of the de novo TERC mutations (G178A and C180T) found uniquely produce a clinical phenotype in the first generation, differing from previously published cases in which individuals in the first generation are usually asymptomatic. Curiously these mutations are located near the triple-helix domain of TERC. We also observed that the recurrent Delta 110-113GACT can present with AA, myelodysplasia or leukemia. The Delta 52-86 is associated with varied phenotypes including pulmonary disease (pulmonary fibrosis) as the first presentation. In summary, this study reports the functional characterization of several novel TERC mutations associated with varied hematologic and extra-hematologic presentations.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据