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|Title:||Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features.|
|Authors:||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|
|Affiliation:||Institute of Human Genetics, University of Ulm, Ulm, Germany|
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
Department of Immunology and Medical Genetics, University of Split, School of Medicine, Split, Croatia
Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt (Main), Germany
Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt (Main), Germany
Department of Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany
Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, La Laguna, Tenerife, Spain
Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australi
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
Department of Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia.
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.
Leibniz Institute for Age Research, Fritz Lippmann Institute, Jena, Germany.
Institute of Genetics, University of Cologne, Cologne, Germany.
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia.
Department of Clinical Genetics, Amsterdam Medical Centre, Amsterdam, the Netherlands.
Department of Pathology, University of Washington, Seattle, Washington, USA.
Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
Neuroscience Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
|Citation:||Nature Genetics 2014; 46(11): 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.|
|Internal ID Number:||25261934|
|Subjects:||Age of Onset|
Fluorescent Antibody Technique
Molecular Sequence Data
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, DNA
|Appears in Collections:||Journal articles|
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