PUBLICATION
Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features
- Authors
- Lessel, D., Vaz, B., Halder, S., Lockhart, P.J., Marinovic-Terzic, I., Lopez-Mosqueda, J., Philipp, M., Sim, J.C., Smith, K.R., Oehler, J., Cabrera, E., Freire, R., Pope, K., Nahid, A., Norris, F., Leventer, R.J., Delatycki, M.B., Barbi, G., von Ameln, S., Högel, J., Degoricija, M., Fertig, R., Burkhalter, M.D., Hofmann, K., Thiele, H., Altmüller, J., Nürnberg, G., Nürnberg, P., Bahlo, M., Martin, G.M., Aalfs, C.M., Oshima, J., Terzic, J., Amor, D.J., Dikic, I., Ramadan, K., Kubisch, C.
- ID
- ZDB-PUB-170214-288
- Date
- 2014
- Source
- Nature Genetics 46: 1239-44 (Journal)
- Registered Authors
- Keywords
- Cancer, Genetics research, Oncogenes
- MeSH Terms
-
- Age of Onset
- Animals
- Base Sequence
- Carcinoma, Hepatocellular/genetics*
- Chromosome Mapping
- Cloning, Molecular
- DNA Primers/genetics
- DNA Replication/genetics
- DNA-Binding Proteins/genetics*
- Flow Cytometry
- Fluorescent Antibody Technique
- Genes, cdc/genetics
- Genomic Instability/genetics*
- Germ-Line Mutation/genetics
- Humans
- Liver Neoplasms/genetics*
- Male
- Molecular Sequence Data
- Pedigree
- Progeria/genetics*
- Reverse Transcriptase Polymerase Chain Reaction
- Sequence Analysis, DNA
- Zebrafish/genetics
- PubMed
- 25261934 Full text @ Nat. Genet.
Citation
Lessel, D., Vaz, B., Halder, S., Lockhart, P.J., Marinovic-Terzic, I., Lopez-Mosqueda, J., Philipp, M., Sim, J.C., Smith, K.R., Oehler, J., Cabrera, E., Freire, R., Pope, K., Nahid, A., Norris, F., Leventer, R.J., Delatycki, M.B., Barbi, G., von Ameln, S., Högel, J., Degoricija, M., Fertig, R., Burkhalter, M.D., Hofmann, K., Thiele, H., Altmüller, J., Nürnberg, G., Nürnberg, P., Bahlo, M., Martin, G.M., Aalfs, C.M., Oshima, J., Terzic, J., Amor, D.J., Dikic, I., Ramadan, K., Kubisch, C. (2014) Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nature Genetics. 46:1239-44.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping