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)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 mutagenesis1,2,3,4,5,6,7. 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.

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Acknowledgements

We are thankful to the family members for participation, G. Gillies for assistance with patient samples, J. Schäfer for zebrafish care and Z. Garajova for technical assistance. We thank A. Ray Chaudhuri for initial help with the DNA fiber assay. We thank F. Böhm, Y. Böge and A. Weber from the University of Zurich and L. Campo and K. Myers from the University of Oxford for providing healthy and HCC human liver biopsies and performing histological and immunohistochemical staining. The zebrafish γ-H2AX antibody was a kind gift of J. Amatruda (University of Texas Southwestern). This work was supported by grants from Deutsche Forschungsgemeinschaft, the Cluster of Excellence 'Macromolecular Complexes' of Goethe University Frankfurt (EXC115), the Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz program Ubiquitin Networks of the State of Hesse, Germany and the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/European Research Council grant agreement number 250241-LineUb to I.D., the European Commission (Marie Curie Reintegration Grant 268333 to M.P.), the Deutsche Stiftung für Herzforschung (M.P.), the Medical Research Council (MC_PC_12001/1) and the Swiss National Science Foundation (31003A_141197) to K.R., grants from the US National Institutes of Health (NIH) National Cancer Institute (R24CA78088 and R24AG042328) to G.M.M., the NIH National Institute on Aging (R21AG033313) to J. Oshima, the Ellison Medical Foundation to J. Oshima, the German Research Foundation (DFG) in the framework of the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases to C.K., an EMBO long-term fellowship to J.L.-M., a grant from the Croatian Ministry of Science, Education and Sport (216-0000000-3348) and a City of Split grant to J.T. and I.D. K.R.S. is supported by a PhD scholarship funded by the Pratt Foundation. M.B. is supported by an Australian Research Council Future Fellowship (FT100100764). P.J.L. is supported by a National Health and Medical Research Council (NHMRC) Career Development Fellowship (APP1032364). This work was made possible through Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme.

Author information

Author notes

    • Davor Lessel
    • , Bruno Vaz
    • , Swagata Halder
    • , Paul J Lockhart
    •  & Ivana Marinovic-Terzic

    These authors contributed equally to this work.

Affiliations

  1. Institute of Human Genetics, University of Ulm, Ulm, Germany.

    • Davor Lessel
    • , Gotthold Barbi
    • , Simon von Ameln
    • , Josef Högel
    •  & Christian Kubisch
  2. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Davor Lessel
    •  & Christian Kubisch
  3. Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.

    • Bruno Vaz
    • , Swagata Halder
    • , Judith Oehler
    •  & Kristijan Ramadan
  4. Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.

    • Swagata Halder
    • , Judith Oehler
    • , Regina Fertig
    •  & Kristijan Ramadan
  5. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

    • Paul J Lockhart
    • , Joe C H Sim
    • , Kate Pope
    • , Martin B Delatycki
    •  & David J Amor
  6. Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.

    • Paul J Lockhart
    • , Richard J Leventer
    • , Martin B Delatycki
    •  & David J Amor
  7. Department of Immunology and Medical Genetics, University of Split, School of Medicine, Split, Croatia.

    • Ivana Marinovic-Terzic
    • , Marina Degoricija
    •  & Janos Terzic
  8. Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt (Main), Germany.

    • Jaime Lopez-Mosqueda
    •  & Ivan Dikic
  9. Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt (Main), Germany.

    • Jaime Lopez-Mosqueda
    •  & Ivan Dikic
  10. Department of Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany.

    • Melanie Philipp
  11. Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.

    • Katherine R Smith
    • , Amsha Nahid
    •  & Melanie Bahlo
  12. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

    • Katherine R Smith
  13. Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, La Laguna, Tenerife, Spain.

    • Elisa Cabrera
    •  & Raimundo Freire
  14. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

    • Fiona Norris
  15. Neuroscience Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.

    • Richard J Leventer
  16. Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.

    • Richard J Leventer
  17. Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia.

    • Martin B Delatycki
  18. Leibniz Institute for Age Research, Fritz Lippmann Institute, Jena, Germany.

    • Martin D Burkhalter
  19. Institute of Genetics, University of Cologne, Cologne, Germany.

    • Kay Hofmann
  20. Cologne Center for Genomics, University of Cologne, Cologne, Germany.

    • Holger Thiele
    • , Janine Altmüller
    • , Gudrun Nürnberg
    •  & Peter Nürnberg
  21. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.

    • Peter Nürnberg
  22. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.

    • Peter Nürnberg
  23. Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia.

    • Melanie Bahlo
  24. Department of Pathology, University of Washington, Seattle, Washington, USA.

    • George M Martin
    •  & Junko Oshima
  25. Department of Clinical Genetics, Amsterdam Medical Centre, Amsterdam, the Netherlands.

    • Cora M Aalfs

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Contributions

D.L., B.V., S.H., P.J.L., I.M.-T., J.L.-M., M.P., J.C.H.S., K.R.S., J. Oehler, K.P., A.N., F.N., R.J.L., M.B.D., G.B., S.v.A., J.H., M.D., R. Fertig, M.D.B., K.H., H.T., J.A., G.N., P.N. and M.B. performed the experiments and did data analysis. E.C., R. Freire, J. Oshima, G.M.M. and C.M.A. contributed materials and reagents used in the study. D.L., K.R. and C.K. wrote the manuscript. J.T., D.J.A., I.D., K.R. and C.K. led and coordinated the entire project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Janos Terzic or David J Amor or Ivan Dikic or Kristijan Ramadan or Christian Kubisch.

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https://doi.org/10.1038/ng.3103

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