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

Item Type:	Article
Title:	Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features
Creators Name:	Lessel, D. and Vaz, B. and Halder, S. and Lockhart, P.J. and Marinovic-Terzic, I. and Lopez-Mosqueda, J. and Philipp, M. and Sim, J.C.H. and Smith, K.R. and Oehler, J. and Cabrera, E. and Freire, R. and Pope, K. and Nahid, A. and Norris, F. and Leventer, R.J. and Delatycki, M. and Barbi, G. and von Ameln, S. and Högel, J. and Degoricija, M. and Fertig, R. and Burkhalter, M.D. and Hofmann, K. and Thiele, H. and Altmüller, J. and Nürnberg, G. and Nürnberg, P. and Bahlo, M. and Martin, G.M. and Aalfs, C.M. and Oshima, J. and Terzic, J. and Amor, D.J. and Dikic, I. and Ramadan, K. and Kubisch, C.
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.
Keywords:	Age of Onset, Base Sequence, Cdc Genes, Chromosome Mapping, DNA Primers, DNA-Binding Proteins, DNA Replication, DNA Sequence Analysis, Flow Cytometry, Fluorescent Antibody Technique, Genomic Instability, Germ-Line Mutation, Hepatocellular Carcinoma, Liver Neoplasms, Molecular Cloning, Molecular Sequence Data, Pedigree, Progeria, Reverse Transcriptase Polymerase Chain Reaction, Animals, Zebrafish
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	46
Number:	11
Page Range:	1239-1244
Date:	November 2014
Official Publication:	https://doi.org/10.1038/ng.3103
PubMed:	View item in PubMed

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