Mutations in SPRTN cause early onset hepatocellular carcinoma, genomicinstability and progeroid features.

Davor Lessel, Bruno Vaz, Swagata Halder, Paul J. Lockhart, Ivana Marinovic-Terzic, Jaime Lopez-Mosqueda, Melanie Philipp, Joe C H. Sim, Katherine R. Smith, Judith Oehler, Elisa Cabrera, Raimundo Freire, Kate Pope, Amsha Nahid, Fiona Norris, Richard J. Leventer, Martin B. Delatycki, Gotthold Barbi, Simon von Ameln, Josef Högel, Marina Degoricija, Regina Fertig, Martin D. Burkhalter, Kay Hofmann, Holger Thiele, Janine Altmüller, Gudrun Nürnberg, Peter Nürnberg, Melanie Bahlo, George M. Martin, Cora M. Aalfs, Junko Oshima, Janos Terzic, David J. Amor, Ivan Dikic, Kristijan Ramadan, Christian Kubisch

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.