Savage Sharon A
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Prog Mol Biol Transl Sci. 2014;125:41-66. doi: 10.1016/B978-0-12-397898-1.00002-5.
Telomeres consist of long nucleotide repeats and a protein complex at chromosome ends essential for chromosome stability. Telomeres shorten with each cell division and thus are markers of cellular age. Dyskeratosis congenita (DC) is a cancer-prone inherited bone marrow failure syndrome caused by germ-line mutations in key telomere biology genes that result in extremely short telomeres. The triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia is diagnostic of DC but highly variable. Patients with DC may also have but numerous other medical problems, including pulmonary fibrosis, liver abnormalities, avascular necrosis of the hips, and stenosis of the esophagus, lacrimal ducts, and/or urethra. All modes of inheritance have been reported in DC and de novo mutations are common. Broad phenotypic heterogeneity occurs within DC. Clinically severe variants of DC are Hoyeraal-Hreidarsson syndrome and Revesz syndrome. Coats plus syndrome joined the spectrum of DC with the discovery that it is caused by mutations in a telomere-capping gene. Less clinically severe variants, such as subsets of apparently isolated aplastic anemia or pulmonary fibrosis, have also been recognized. These patients may not have the DC-associated mucocutaneous triad or complicated medical features, but they do have the same underlying genetic etiology. This has led to the use of the descriptive term telomere biology disorder (TBD). This chapter will review the connection between telomere biology and human disease through the examples of DC and its related TBDs.
端粒由长核苷酸重复序列和位于染色体末端的蛋白质复合体组成，对染色体稳定性至关重要。端粒随细胞每次分裂而缩短，因此是细胞衰老的标志物。先天性角化不良（DC）是一种易患癌症的遗传性骨髓衰竭综合征，由关键端粒生物学基因的种系突变引起，导致端粒极短。指甲发育异常、皮肤色素沉着异常和口腔白斑三联征可诊断DC，但表现差异很大。DC患者还可能有许多其他医学问题，包括肺纤维化、肝脏异常、髋关节缺血性坏死以及食管、泪管和/或尿道狭窄。DC已报道了所有遗传方式，新发突变很常见。DC存在广泛的表型异质性。DC临床上严重的变异型是霍耶拉尔 - 赫雷达尔松综合征和雷维斯综合征。随着发现科茨加综合征由端粒封端基因突变引起，它也被纳入DC谱系。临床症状较轻的变异型，如明显孤立的再生障碍性贫血或肺纤维化的亚型，也已被认识到。这些患者可能没有与DC相关的黏膜皮肤三联征或复杂的医学特征，但他们有相同的潜在遗传病因。这导致了使用描述性术语端粒生物学障碍（TBD）。本章将通过DC及其相关TBDs的例子回顾端粒生物学与人类疾病之间的联系。
