A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.
A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.
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DOI：
10.1371/journal.pgen.1003695
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发表时间：
2013-08
期刊：
影响因子：
4.5
通讯作者：
Petrini JH
中科院分区：
文献类型：
--
作者：
Ballew BJ;Joseph V;De S;Sarek G;Vannier JB;Stracker T;Schrader KA;Small TN;O'Reilly R;Manschreck C;Harlan Fleischut MM;Zhang L;Sullivan J;Stratton K;Yeager M;Jacobs K;Giri N;Alter BP;Boland J;Burdett L;Offit K;Boulton SJ;Savage SA;Petrini JH
先天性角化异常（DC）是一种异质性遗传骨髓衰竭和癌症易感性综合征，其中端粒生物学基因的种系突变约占已知家族的一半。Hoyeraal - Hreidarsson综合征（HH）是DC的一种临床严重变体，患者还伴有小脑发育不全，并可能出现严重的免疫缺陷和肠病。我们在两个无血缘关系的德系犹太人（AJ）祖先家族中发现了RTEL1常染色体隐性突变，RTEL1是一种具有关键端粒功能的解旋酶。这些家庭中的受影响个体是同一突变R1264H的纯合子，该突变影响RTEL1的三个同工型。每个亲本是一个突变等位基因的杂合载体。患者来源的细胞系显示端粒功能障碍的证据，包括端粒长度显着减少，端粒长度异质性和染色体外环状端粒DNA的存在。此外，RTEL1突变细胞对链间交联剂丝裂霉素c的敏感性增强。分子数据和遗传模式与RTEL1的亚形态突变一致，这是临床和细胞表型的基础。这项研究进一步表明RTEL1与DC/HH和免疫缺陷的病因学有关，并确定了RTEL1中已知的第一个纯合子常染色体隐性遗传病相关突变。先天性角化不良（DC）是一种罕见的遗传性疾病，其患者发生癌症和骨髓衰竭的风险非常高。DC的临床特征包括指甲异常、皮肤变色和口腔白斑。Hoyeraal-Hreidarsson综合征（HH）患者有DC加小脑发育不全、免疫缺陷和产前生长不良的症状。DC和HH是端粒生物学缺陷引起的；端粒维持不当被认为是致癌的主要因素。在一半的DC病例中，致病突变是未知的。通过研究尚未发现致病突变的DC家族，我们发现了RTEL1的纯合子种系突变，RTEL1是一种端粒维持基因，如果发生突变，可导致HH。突变导致RTEL1蛋白无法在端粒中正常工作，并强调了其在端粒生物学中的重要作用。
Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1. Patients with dyskeratosis congenita (DC), a rare inherited disease, are at very high risk of developing cancer and bone marrow failure. The clinical features of DC include nail abnormalities, skin discoloration, and white spots in the mouth. Patients with Hoyeraal-Hreidarsson syndrome (HH) have symptoms of DC plus cerebellar hypoplasia, immunodeficiency, and poor prenatal growth. DC and HH are caused by defects in telomere biology; improperly maintained telomeres are thought to be a major contributor to carcinogenesis. In half the cases of DC, the causative mutation is unknown. By studying families affected by DC for whom a causative mutation has not yet been identified, we have discovered a homozygous germline mutation in RTEL1, a telomere maintenance gene that, if mutated, can result in HH. The mutations result in the inability of the RTEL1 protein to function properly at the telomere, and underscore its important role in telomere biology.