Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

被引：172

作者：

Lessel, Davor ^{[1
,2
]}

Vaz, Bruno ^{[3
,4
]}

Halder, Swagata ^{[3
,4
,5
]}

Lockhart, Paul J. ^{[6
,7
]}

Marinovic-Terzic, Ivana ^{[8
]}

Lopez-Mosqueda, Jaime ^{[9
,10
]}

Philipp, Melanie ^{[11
]}

Sim, Joe C. H. ^{[6
]}

Smith, Katherine R. ^{[12
,13
]}

Oehler, Judith ^{[3
,4
,5
]}

Cabrera, Elisa ^{[14
]}

Freire, Raimundo ^{[14
]}

Pope, Kate ^{[6
]}

Nahid, Amsha ^{[12
]}

Norris, Fiona ^{[15
]}

Leventer, Richard J. ^{[7
,16
,17
]}

Delatycki, Martin B. ^{[6
,7
,18
]}

Barbi, Gotthold ^{[1
]}

von Ameln, Simon ^{[1
]}

Hoegel, Josef ^{[1
]}

Degoricija, Marina ^{[8
]}

Fertig, Regina ^{[5
]}

Burkhalter, Martin D. ^{[19
]}

Hofmann, Kay ^{[20
]}

Thiele, Holger ^{[20
,21
]}

Altmueller, Janine ^{[20
,21
]}

Nuernberg, Gudrun ^{[20
,21
]}

Nuernberg, Peter ^{[20
,21
,22
,23
]}

Bahlo, Melanie ^{[12
,14
,24
]}

Martin, George M. ^{[25
]}

Aalfs, Cora M. ^{[26
]}

Oshima, Junko ^{[25
]}

Terzic, Janos ^{[8
]}

Amor, David J. ^{[6
,7
]}

Dikic, Ivan ^{[9
,10
]}

Ramadan, Kristijan ^{[3
,4
,5
]}

Kubisch, Christian ^{[1
,2
]}

机构：

[1] Univ Ulm, Inst Human Genet, D-89069 Ulm, Germany

[2] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, Hamburg, Germany

[3] Univ Oxford, Canc Res UK, Oxford, England

[4] Univ Oxford, MRC, Oxford Inst Radiat Oncol, Dept Oncol, Oxford, England

[5] Univ Zurich Vetsuisse, Inst Pharmacol & Toxicol, Zurich, Switzerland

[6] Murdoch Childrens Res Inst, Bruce Lefroy Ctr Genet Hlth Res, Parkville, Vic, Australia

[7] Univ Melbourne, Dept Paediat, Parkville, Vic 3052, Australia

[8] Univ Split, Sch Med, Dept Immunol & Med Genet, Split, Croatia

[9] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, D-60054 Frankfurt, Germany

[10] Goethe Univ Frankfurt, Sch Med, Inst Biochem 2, D-60054 Frankfurt, Germany

[11] Univ Ulm, Dept Biochem & Mol Biol, D-89069 Ulm, Germany

[12] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic, Australia

[13] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia

[14] Hosp Univ Canarias, Unidad Invest, Inst Tecnol Biomed, Tenerife, Spain

[15] Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Parkville, Vic, Australia

[16] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia

[17] Royal Childrens Hosp, Dept Neurol, Parkville, Vic 3052, Australia

[18] Austin Hlth, Austin, Australia

[19] Fritz Lippmann Inst, Leibniz Inst Age Res, Jena, Germany

[20] Univ Cologne, Inst Genet, Cologne, Germany

[21] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany

[22] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany

[23] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany

[24] Univ Melbourne, Dept Math & Stat, Parkville, Vic 3052, Australia

[25] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[26] Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

来源：

NATURE GENETICS | 2014年 / 46卷 / 11期

基金：

美国国家卫生研究院; 澳大利亚研究理事会; 瑞士国家科学基金会; 欧洲研究理事会; 英国医学研究理事会;

关键词：

DNA-DAMAGE; REPLICATION-FORK; TRANSLESION SYNTHESIS; DVC1; C1ORF124; SPARTAN/C1ORF124; CANCER; REGULATOR; CHECKPOINT; STRESS; GENE;

D O I：

10.1038/ng.3103

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1)(1-7) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis(1-7). Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.

引用

页码：1239 / 1244

页数：6

共 32 条

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