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

Kristijan Ramadan and colleagues report the identification of three individuals from two families with biallelic inactivating mutations in SPRTN causing early onset hepatocellular carcinoma and defects in the DNA replication stress response. Functional studies confirmed critical roles for SPRTN in G2/M checkpoint response and DNA replication. 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 , 2 , 3 , 4 , 5 , 6 , 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 , 2 , 3 , 4 , 5 , 6 , 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.