Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.
Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.
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DOI：
10.1101/gad.248567.114
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发表时间：
2014-10-01
影响因子：
10.5
通讯作者：
Savage SA
中科院分区：
文献类型：
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作者：
Kocak H;Ballew BJ;Bisht K;Eggebeen R;Hicks BD;Suman S;O'Neil A;Giri N;NCI DCEG Cancer Genomics Research Laboratory;NCI DCEG Cancer Sequencing Working Group;Maillard I;Alter BP;Keegan CE;Nandakumar J;Savage SA
端粒生物学基因的生殖系突变导致先天性角化不良（DC），一种遗传性骨髓衰竭和癌症易感综合征。Hoyeraal-Hreidarsson综合征（HH）是DC的一种临床严重变异。使用外显子组测序，Kocak等人在一个受HH影响的家族中鉴定了ACD（编码TPP 1）的突变，该突变是端粒shelterin复合物的一种组分。突变的表征显示，影响TPP 1蛋白的TEL贴片表面的单个氨基酸缺失显著损害端粒酶募集和持续合成能力。端粒生物学基因的生殖系突变导致先天性角化不良（DC），一种遗传性骨髓衰竭和癌症易感综合征。DC是一种临床异质性疾病，通过发育不良的指甲、异常皮肤色素沉着和口腔白斑三联征诊断; Hoyeraal-Hreidarsson综合征（HH）是DC的一种临床严重变体，还包括小脑发育不全、免疫缺陷和宫内生长迟缓。大约70%的DC病例与9个基因之一的种系突变有关，这些基因的产物都涉及端粒生物学。使用外显子组测序，我们确定了一个受HH影响的家族中肾上腺皮质发育不良同源物（ACD）（编码TPP 1）的突变，该突变是端粒庇护素复合物的一个组成部分。先证者遗传了父亲的缺失和母亲的错义突变，导致端粒极短和严重的临床表型。突变的表征显示，影响TPP 1蛋白的TEL贴片表面的单个氨基酸缺失显著损害端粒酶募集和持续合成能力，而TPP 1的TIN 2结合区中的错义突变对TPP 1功能没有明显的有害作用。我们的研究结果强调了TEL补丁在适当的干细胞功能中的关键作用，并证明了TPP 1是第二个shelterin成分（除了TIN 2）涉及DC。
Germline mutations in telomere biology genes cause dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome. Hoyeraal-Hreidarsson syndrome (HH) is a clinically severe variant of DC. Using exome sequencing, Kocak et al. identified mutations in ACD (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by HH. Characterization of the mutations revealed that the single-amino-acid deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity. Germline mutations in telomere biology genes cause dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome. DC is a clinically heterogeneous disorder diagnosed by the triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia; Hoyeraal-Hreidarsson syndrome (HH), a clinically severe variant of DC, also includes cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation. Approximately 70% of DC cases are associated with a germline mutation in one of nine genes, the products of which are all involved in telomere biology. Using exome sequencing, we identified mutations in Adrenocortical Dysplasia Homolog (ACD) (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by HH. The proband inherited a deletion from his father and a missense mutation from his mother, resulting in extremely short telomeres and a severe clinical phenotype. Characterization of the mutations revealed that the single-amino-acid deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity, while the missense mutation in the TIN2-binding region of TPP1 is not as clearly deleterious to TPP1 function. Our results emphasize the critical roles of the TEL patch in proper stem cell function and demonstrate that TPP1 is the second shelterin component (in addition to TIN2) to be implicated in DC.
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影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
DOI：
10.1182/asheducation-2011.1.480
发表时间：
2011-12-01
期刊：
HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM
影响因子：
--
作者：
Dokal, Inderjeet
通讯作者：
Dokal, Inderjeet
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
3.5
作者：
Keegan, CE;Hutz, JE;Hammer, GD
通讯作者：
Hammer, GD
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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