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

Lessel, D; Vaz, B; Halder, S; Lockhart, PJ; Marinovic-Terzic, I; Lopez-Mosqueda, J; Philipp, M; Sim, JC; Smith, KR; Oehler, J; Cabrera, E; Freire, R; Pope, K; Nahid, A; Norris, F; Leventer, RJ; Delatycki, MB; Barbi, G; von Ameln, S; Hogel, J; Degoricija, M; Fertig, R; Burkhalter, MD; Hofmann, K; Thiele, H; Altmuller, J; Nurnberg, G; Nurnberg, P; Bahlo, M; Martin, GM; Aalfs, CM; Oshima, J; Terzic, J; Amor, DJ; Dikic, I; Ramadan, K; Kubisch, C

Author(s): Lessel, D; Vaz, B; Halder, S; Lockhart, PJ; Marinovic-Terzic, I; Lopez-Mosqueda, J; Philipp, M; Sim, JC; Smith, KR; Oehler, J; Cabrera, E; Freire, R; Pope, K; Nahid, A; Norris, F; Leventer, RJ; Delatycki, MB; Barbi, G; von Ameln, S; Hogel, J; Degoricija, M; Fertig, R; Burkhalter, MD; Hofmann, K; Thiele, H; Altmuller, J; Nurnberg, G; Nurnberg, P; Bahlo, M; Martin, GM; Aalfs, CM; Oshima, J; Terzic, J; Amor, DJ; Dikic, I; Ramadan, K; Kubisch, C;
Details: Publication Year 2014-09-28,Volume 46,Issue #11,Page 1239-1244
Journal Title: Nat Genet
Publication Type: Journal Article
Abstract: 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) 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. 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.
Publisher: NPG
Research Division(s): Bioinformatics
Publisher's Version: https://doi.org/10.1038/ng.3103
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2014-10-13 02:21:51