Young Neal S
Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
Hematology. 2012 Apr;17 Suppl 1:S18-21. doi: 10.1179/102453312X13336169155132.
The telomeropathies are a newly described group of human diseases based on the genetics and molecular biology of the telomeres, the ends of chromosomes. Telomeres are repeated hexanucleotides and their associated proteins; the protect chromosomes from recognition as damaged DNA, and their inevitable gradual loss with DNA replication is harmless as they are noncoding. However, when telomeres become critically short in a cell, senescence, apoptosis, or, rarely malignant transformation results. In individuals with mutations in genes involved in telomere repair, especially the enzymatic telomerase complex, telomere attrition is accelerated. Severe deficiencies result in dyskeratosis congenita, a congenital aplastic anemia with associated mucocutaneous abnormalities. Mutations in TERT, the catalytic component, and TERC, the RNA template, can behave as risk factors for the development of bone marrow failure, pulmonary fibrosis, and hepatic cirrhosis. Both penetrance and organ specificity are variable and not well understood. Chromosome instability is a result of critical shortening of telomeres and cancer. For example, short telomeres are the major prognostic risk factor for clonal evolution to myelodysplasia and acute leukemia. Practically, hematologists need to recognize the multisystem presentation of telomere disease, implications for outcomes, and options for therapy.
端粒病是基于染色体末端端粒的遗传学和分子生物学新描述的一组人类疾病。端粒是重复的六核苷酸及其相关蛋白；它们保护染色体不被识别为受损DNA，并且随着DNA复制它们不可避免地逐渐缩短是无害的，因为它们是非编码的。然而，当细胞中端粒变得极短时，会导致细胞衰老、凋亡，或很少发生恶性转化。在参与端粒修复的基因发生突变的个体中，尤其是在酶促端粒酶复合物中，端粒磨损会加速。严重缺陷会导致先天性角化不良，这是一种伴有黏膜皮肤异常的先天性再生障碍性贫血。催化成分TERT和RNA模板TERC中的突变可作为骨髓衰竭、肺纤维化和肝硬化发展的危险因素。外显率和器官特异性都是可变的，且尚未得到很好的理解。染色体不稳定是端粒严重缩短和癌症的结果。例如，短端粒是克隆演变为骨髓增生异常综合征和急性白血病的主要预后危险因素。实际上，血液学家需要认识到端粒疾病的多系统表现、对预后的影响以及治疗选择。
