Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Lookup NU author(s): Dr Brian Wilson


Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


© 2020 Crown copyright. The government of Australia, Canada, or the UK ("the Crown") owns the copyright interests of authors who are government employees. The Crown Copyright is not transferable.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.

Publication metadata

Author(s): Apelt K, White SM, Kim HS, Yeo J-E, Kragten A, Wondergem AP, Rooimans MA, Gonzalez-Prieto R, Wiegant WW, Lunke S, Flanagan D, Pantaleo S, Quinlan C, Hardikar W, van Attikum H, Vertegaal ACO, Wilson BT, Wolthuis RMF, Scharer OD, Luijsterburg MS

Publication type: Article

Publication status: Published

Journal: Journal of Experimental Medicine

Year: 2021

Volume: 218

Issue: 3

Print publication date: 01/03/2021

Online publication date: 14/12/2020

Acceptance date: 15/10/2020

ISSN (print): 0022-1007

ISSN (electronic): 1540-9538

Publisher: Rockefeller University Press


DOI: 10.1084/jem.20200622

PubMed id: 33315086


Altmetrics provided by Altmetric