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

2014-09-28

Lessel, Davor

Vaz, Bruno

Halder, Swagata

Lockhart, Paul J

Marinovic-Terzic, Ivana

Lopez-Mosqueda, Jaime

Philipp, Melanie

Sim, Joe C H

Smith, Katherine R

Oehler, Judith

Cabrera, Elisa

Freire, Raimundo

Pope, Kate

Nahid, Amsha

Norris, Fiona

Leventer, Richard J

Delatycki, Martin B

Barbi, Gotthold

von Ameln, Simon

Högel, Josef

Degoricija, Marina

Fertig, Regina

Burkhalter, Martin D

Hofmann, Kay

Thiele, Holger

Altmüller, Janine

Nürnberg, Gudrun

Nürnberg, Peter

Bahlo, Melanie

Martin, George M

Aalfs, Cora M

Oshima, Junko

Terzic, Janos

Amor, David John

Dikic, Ivan

Ramadan, Kristijan

Kubisch, Christian

Journal Article

10.1038/ng.3103

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.

link

Nature Genetics 2014; 46(11): 1239-44

Nature genetics