TERT c.3150 G > C (p.K1050N): a founder Ashkenazi Jewish variant associated with telomere biology disorders.

IF 4.8 2区医学 Q1 GENETICS & HEREDITY

NPJ Genomic Medicine Pub Date : 2025-06-02 DOI:10.1038/s41525-025-00501-8

Kelvin César de Andrade, Emilia M Pinto, Tianna Zhao, Logan P Zeigler, Jung Kim, Neelam Giri, Jeremy S Haley, Lisa J McReynolds, Oscar Florez-Vargas, Aaron H Phillips, Richard W Kriwacki, Sherifa A Akinniyi, Scott B Cohen, Matthew R Emerson, Diane T Smelser, Gretchen M Urban, Cintia Fridman, Gerard P Zambetti, Tracy M Bryan, David J Carey, Christine Kim Garcia, Douglas R Stewart, Sharon A Savage

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引用次数: 0

Abstract

Pathogenic germline variants in telomerase (TERT) cause telomere biology disorders (TBDs) and are associated with bone marrow failure, pulmonary fibrosis, and other complications. TERT c.3150 G > C (p.K1050N) is frequent in the Ashkenazi Jewish (ASH) population and has been identified in ASH families with TBDs. Whole-genome sequencing of 96 p.K1050N heterozygotes from the UK Biobank and All of Us databases revealed a shared haplotype block, supporting a founder effect. Analyses of 15 additional p.K1050N cases validated this haplotype and identified mitochondrial and Y-STR haplogroups consistent with ASH ancestry. Clinical assessments showed that p.K1050N contributes to TBD phenotypes and shortened telomeres, while population data suggest incomplete penetrance. p.K1050N reduces telomerase activity and processivity, and decreases PCNA expression and BrdU incorporation, impairing cell proliferation. Our findings establish TERT p.K1050N as an ASH founder variant associated with TBDs, underscoring the need for genetic screening and long-term clinical studies.

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TERT C .3150 G > C (p.K1050N)：与端粒生物学疾病相关的德系犹太人始祖变异。

端粒酶（TERT）的致病性种系变异引起端粒生物学紊乱（tbd），并与骨髓衰竭、肺纤维化和其他并发症相关。TERT C .3150 G > C （p.K1050N）常见于德系犹太人（ASH）人群，并已在患有tbd的ASH家庭中发现。来自UK Biobank和All of Us数据库的96个p.K1050N杂合子的全基因组测序显示了一个共享的单倍型块，支持创始人效应。对另外15例p.K1050N病例的分析证实了该单倍型，并鉴定出与ASH祖先一致的线粒体和Y-STR单倍群。临床评估显示p.K1050N与TBD表型和端粒缩短有关，而人口数据显示不完全外显。p.K1050N降低端粒酶活性和加工性，降低PCNA表达和BrdU掺入，损害细胞增殖。我们的研究结果表明，TERT p.K1050N是与tbd相关的ASH创始变异，强调了遗传筛查和长期临床研究的必要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

1.90%

发文量

审稿时长

17 weeks

期刊介绍： npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.