Journal article

ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients

Katja Apelt, Susan M White, Hyun Suk Kim, Jung-Eun Yeo, Angela Kragten, Annelotte P Wondergem, Martin A Rooimans, Roman Gonzalez-Prieto, Wouter W Wiegant, Sebastian Lunke, Daniel Flanagan, Sarah Pantaleo, Catherine Quinlan, Winita Hardikar, Haico van Attikum, Alfred CO Vertegaal, Brian T Wilson, Rob MF Wolthuis, Orlando D Scharer, Martijn S Luijsterburg



ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER), interstrand cross-link (ICL) repair, and DNA double-strand break (DSB) repair. Only two patients with bi-allelic ERCC1 mutations have been reported, both of whom had features of Cockayne syndrome and died in infancy. Here, we describe two siblings with bi-allelic ERCC1 mutations in their teenage years. Genomic sequencing identified a deletion and a missense variant (R156W) within ERCC1 that disrupts a salt bridge below the XPA-binding pocket. Patient-derived fibroblasts and knock-in epithelial cells carrying the R156W substitution show dramatically reduced protein levels of ERCC1 and XPF. Moreover, muta..

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Awarded by Nederlandse Organisatie voor Wetenschappelijk Onderzoek VIDI grant

Awarded by European Research Council

Awarded by Vertegaal, KWF Kankerbestrijding Young Investigator grant

Awarded by Korean Institute for Basic Science

Awarded by National Cancer Institute

Funding Acknowledgements

The authors acknowledge both siblings and their parents for contributing to this paper, Sylvie Noordermeer (Leiden University Medical Center [LUMC] , Leiden, Netherlands) for the pLenti-CW57-TO-GFP lentiviral expression vector and advice on generating KI cells, Joachim Goedhart (University of Amsterdam, Amsterdam, Netherlands) for the mVenus cDNA, Bert van der Kooij (LUMC, Leiden, Netherlands) for the DNA-PK inhibitor, Wim Vermeulen and Anja Raams (Erasmus MC, Rotterdam, Netherlands) for providing 165TOR cells, Tomoo Ogi (University of Nagoya, Japan) for providing CS20LO cells, Alan Lehman (University of Sussex, UK) for providing CSL16NG and CSL16NGhTERT cells, and Joost Schimmel (LUMC, Leiden, Netherlands) for advice on generating KI cells. This work was funded by a Leiden University Medical Center Research Fellowship and a Nederlandse Organisatie voor Wetenschappelijk Onderzoek VIDI grant (ALW.016.161.320) to M.S. Luijsterburg, a European Research Council starting grant (310913) to A.C.O. Vertegaal, a KWF Kankerbestrijding Young Investigator grant (11367) to R. Gonzalez-Prieto, a KWF Kankerbestrijding grant (VU 2013-5983) to M.A. Rooimans, and grants from the Korean Institute for Basic Science (IBS-R022-A1) and the National Cancer Institute (P01CA092584) to O.D. Schadrer.