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, Román González-Prieto, Wouter W. Wiegant, Sebastian Lunke, Daniel Flanagan, Sarah Pantaleo, Catherine Quinlan, Winita Hardikar, Haico van Attikum, Alfred C. O. Vertegaal, Brian T. Wilson, Rob M. F. Wolthuis, Orlando D. Schärer, Martijn S. Luijsterburg

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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, mutant ERCC1 weakly interacts with NER and ICL repair proteins, resulting in diminished recruitment to DNA damage. Consequently, patient cells show strongly reduced NER activity and increased chromosome breakage induced by DNA cross-linkers, while DSB repair was relatively normal. We report a new case of ERCC1 deficiency that severely affects NER and considerably impacts ICL repair, which together result in a unique phenotype combining short stature, photosensitivity, and progressive liver and kidney dysfunction.
Original languageEnglish
Article numbere20200622
JournalJournal of Experimental Medicine
Issue number3
Publication statusPublished - 1 Mar 2021

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