First Reported Patient with Human ERCC1 Deficiency Has Cerebro-Oculo-Facio-Skeletal Syndrome with a Mild Defect in Nucleotide Excision Repair and Severe Developmental Failure

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.

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

“…The similar neuropathologies in COFS, CS, and AGS have been noted previously by others [19,70]. COFS can also result from mutations in XPD [71], XPG [72], or ERCC1 [73], but neuropathological information on these cases is limited.…”

Hyper telomere recombination accelerates replicative senescence and may promote premature aging

“…34. Primary human fibroblasts from ERCC1 patient 165TOR were obtained and maintained as previously described (37). All cell lines were incubated at 37°C in an atmosphere of 95% air and 5% carbon dioxide.…”

“…Similarly, deletion of Ercc1 by transfecting Ercc1 −/cond mouse embryonic stem cells with a plasmid expressing Cre was not achieved in over 1,000 clones screened. As further testament to the requirement for ERCC1 for survival, only one patient with a mutation in ERCC1 has been reported to date (37).…”

“…We sought to evaluate the role of ERCC1 in T-SCE recombination in primary cells from the ERCC1 patient, 165TOR, who despite mutations in the gene, maintained diminished but detectable ERCC1-XPF nuclease activity, allowing survival until 14 mo of age (37). The 165TOR cells grew poorly, even in a lowoxygen environment, but sufficient metaphase spreads for T-SCE analysis were obtained.…”

Papel das proteínas XPD e DNA polimerase eta nas respostas de células humanas a danos no genoma

“…COFS é caracterizada por sintomas do tipo CS II, além de artrogripose (deficiências nas articulações e na musculatura), microcefalia, catarata e microftalmia; esses sintomas apresentam-se mesmo antes do nascimento, e levam a uma expectativa de vida extremamente curta. Os pacientes COFS apresentam mutações em CSB (Meira et al, 2000), XPD (Graham et al, 2001), XPG (Hamel et al, 1996) ou ERCC1 (Jaspers et al, 2007). UVSS é caracterizada somente por fotossensibilidade, sem nenhum outro sintoma de CS, nem aumento na incidência de desenvolvimento de câncer; os pacientes UVSS podem ser mutações em CSA (Nardo et al, 2009), CSB (Horibata et al, 2004) ou UVSSA (Nakazawa et al 2012;Schwertman et al, 2012;Zhang et al, 2012).…”