title: Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features.
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.
authors.affiliation: 1] Institute of Human Genetics, University of Ulm, Ulm, Germany. [2] Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Davor
authors.initials: D
authors.lastname: Lessel
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vaz
authors.affiliation: 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.
authors.forename: Swagata
authors.initials: S
authors.lastname: Halder
authors.affiliation: 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.
authors.forename: Paul J
authors.identifier: 0000000325318413
authors.initials: PJ
authors.lastname: Lockhart
authors.affiliation: Department of Immunology and Medical Genetics, University of Split, School of Medicine, Split, Croatia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Marinovic-Terzic
authors.affiliation: 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.
authors.forename: Jaime
authors.initials: J
authors.lastname: Lopez-Mosqueda
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Philipp
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Joe C H
authors.initials: JC
authors.lastname: Sim
authors.affiliation: 1] Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia. [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Katherine R
authors.identifier: 0000000203295938
authors.initials: KR
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Judith
authors.initials: J
authors.lastname: Oehler
authors.affiliation: Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, La Laguna, Tenerife, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cabrera
authors.affiliation: Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, La Laguna, Tenerife, Spain.
authors.forename: Raimundo
authors.initials: R
authors.lastname: Freire
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Pope
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
authors.forename: Amsha
authors.initials: A
authors.lastname: Nahid
authors.affiliation: Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: Norris
authors.affiliation: 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.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.affiliation: 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.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Delatycki
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Gotthold
authors.initials: G
authors.lastname: Barbi
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: von Ameln
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Högel
authors.affiliation: Department of Immunology and Medical Genetics, University of Split, School of Medicine, Split, Croatia.
authors.forename: Marina
authors.initials: M
authors.lastname: Degoricija
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.
authors.forename: Regina
authors.initials: R
authors.lastname: Fertig
authors.affiliation: Leibniz Institute for Age Research, Fritz Lippmann Institute, Jena, Germany.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Burkhalter
authors.affiliation: Institute of Genetics, University of Cologne, Cologne, Germany.
authors.forename: Kay
authors.identifier: 0000000222899083
authors.initials: K
authors.lastname: Hofmann
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: 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.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Martin
authors.affiliation: Department of Clinical Genetics, Amsterdam Medical Centre, Amsterdam, the Netherlands.
authors.forename: Cora M
authors.initials: CM
authors.lastname: Aalfs
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Oshima
authors.affiliation: Department of Immunology and Medical Genetics, University of Split, School of Medicine, Split, Croatia.
authors.forename: Janos
authors.initials: J
authors.lastname: Terzic
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.affiliation: 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.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.affiliation: 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.
authors.forename: Kristijan
authors.initials: K
authors.lastname: Ramadan
authors.affiliation: 1] Institute of Human Genetics, University of Ulm, Ulm, Germany. [2] Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
mesh_terms: D017668:Age of Onset; D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018816:Genes, cdc / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D011371:Progeria / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015027:Zebrafish / Q000235:genetics
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; C574636:SPRTN protein, human