2. Academic Validation
  3. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

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

  • Nat Genet. 2014 Nov;46(11):1239-44. doi: 10.1038/ng.3103.
Davor Lessel 1,  Bruno Vaz 2,  Swagata Halder 3,  Paul J Lockhart 4,  Ivana Marinovic-Terzic 5,  Jaime Lopez-Mosqueda 6,  Melanie Philipp 7,  Joe C H Sim 8,  Katherine R Smith 9,  Judith Oehler 3,  Elisa Cabrera 10,  Raimundo Freire 10,  Kate Pope 8,  Amsha Nahid 11,  Fiona Norris 12,  Richard J Leventer 13,  Martin B Delatycki 14,  Gotthold Barbi 15,  Simon von Ameln 15,  Josef Högel 15,  Marina Degoricija 5,  Regina Fertig 16,  Martin D Burkhalter 17,  Kay Hofmann 18,  Holger Thiele 19,  Janine Altmüller 19,  Gudrun Nürnberg 19,  Peter Nürnberg 20,  Melanie Bahlo 21,  George M Martin 22,  Cora M Aalfs 23,  Junko Oshima 22,  Janos Terzic 5,  David J Amor 4,  Ivan Dikic 6,  Kristijan Ramadan 3,  Christian Kubisch 1
Affiliations

Affiliations

  • 1 1] Institute of Human Genetics, University of Ulm, Ulm, Germany. [2] Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 2 Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
  • 3 1] Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK. [2] Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.
  • 4 1] Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia. [2] Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
  • 5 Department of Immunology and Medical Genetics, University of Split, School of Medicine, Split, Croatia.
  • 6 1] Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt (Main), Germany. [2] Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt (Main), Germany.
  • 7 Department of Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany.
  • 8 Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
  • 9 1] Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia. [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
  • 10 Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, La Laguna, Tenerife, Spain.
  • 11 Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
  • 12 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
  • 13 1] Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia. [2] Neuroscience Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia. [3] Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.
  • 14 1] Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia. [2] Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia. [3] Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia.
  • 15 Institute of Human Genetics, University of Ulm, Ulm, Germany.
  • 16 Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.
  • 17 Leibniz Institute for Age Research, Fritz Lippmann Institute, Jena, Germany.
  • 18 Institute of Genetics, University of Cologne, Cologne, Germany.
  • 19 Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • 20 1] Cologne Center for Genomics, University of Cologne, Cologne, Germany. [2] Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. [3] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • 21 1] Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia. [2] Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia.
  • 22 Department of Pathology, University of Washington, Seattle, Washington, USA.
  • 23 Department of Clinical Genetics, Amsterdam Medical Centre, Amsterdam, the Netherlands.
PMID: 25261934 DOI: 10.1038/ng.3103
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.

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