Abstract
Nucleotide excision repair (NER) is a genome caretaker mechanism responsible for removing helix-distorting DNA lesions, most notably ultraviolet photodimers. Inherited defects in NER result in profound photosensitivity and the cancer-prone syndrome xeroderma pigmentosum (XP) or two progeroid syndromes: Cockayne and trichothiodystrophy syndromes. The heterodimer ERCC1-XPF is one of two endonucleases required for NER. Mutations in XPF are associated with mild XP and rarely with progeria. Mutations in ERCC1 have not been reported. Here, we describe the first case of human inherited ERCC1 deficiency. Patient cells showed moderate hypersensitivity to ultraviolet rays and mitomycin C, yet the clinical features were very severe and, unexpectedly, were compatible with a diagnosis of cerebro-oculo-facio-skeletal syndrome. This discovery represents a novel complementation group of patients with defective NER. Further, the clinical severity, coupled with a relatively mild repair defect, suggests novel functions for ERCC1.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 457-466 |
| Number of pages | 10 |
| Journal | American Journal of Human Genetics |
| Volume | 80 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2007 |
| Externally published | Yes |
Bibliographical note
Funding Information:We express our gratitude to Drs. J. M. Egly, O. Schärer, and G. Breedveld, for purified protein preparations, antibodies, and a standard set of human genomes, respectively. This work was supported by Radiosensitivity of Individuals and Sensitivity Induced by Ionizing Radiation grant EU-MRTN-CT-2003-503618, Netherlands Organisation for Scientific Research Vidi grant 917.46.364, ZonMW project 912.03.012, and American Institute for Cancer Research grant ICR 05-045. L.J.N. and A.R.R. were supported by National Cancer Institute grant CA111525-01 and Ellison Medical Foundation grant AG-NS-0303-05.
