Heterogeneity and overlaps in nucleotide excision repair disorders

Abstract

Nucleotide excision repair (NER) is an essential DNA repair pathway devoted to the removal of bulky lesions such as photoproducts induced by the ultraviolet (UV) component of solar radiation. Deficiencies in NER typically result in a group of heterogeneous distinct disorders ranging from the mild UV sensitive syndrome to the cancer-prone xeroderma pigmentosum and the neurodevelopmental/progeroid conditions trichothiodystrophy, Cockayne syndrome and cerebro-oculo-facio-skeletalsyndrome. A complicated genetic scenario underlines these disorders with the same gene linked to different clinical entities as well as different genes associated with the same disease. Overlap syndromes with combined hallmark features of different NER disorders can occur and sporadic presentations showing extra features of the hematological disorder Fanconi Anemia or neurological manifestations mimicking Hungtinton disease-like syndromes have been described. Here, we discuss the multiple functions of the five major pleiotropic NER genes (ERCC3/XPB, ERCC2/XPD, ERCC5/ XPG, ERCC1 and ERCC4/XPF) and their relevance in phenotypic complexity. We provide an update of mutational spectra and examine genotype-phenotype relationships.Finally, the molecular defects that could explain the puzzling overlap syndromes are discussed. K E Y W O R D Sgenotype-phenotype relationships, NER disorders, nucleotide excision repair (NER), overlap syndromes

Nucleolar and Ribosomal Dysfunction—A Common Pathomechanism in Childhood Progerias?

“…The CS is a rare autosomal recessive disease that can be caused by six different genes, which are all involved in nucleotide excision repair (NER) of UV lesions [34]. It is characterized by a high skin UV sensitivity and severe developmental and degenerative disturbances with a mean life expectancy of 12 years [35,36].…”

Expansion of the clinical and molecular spectrum of an XPD‐related disorder linked to biallelic mutations in ERCC2 gene

“…Biallelic mutations in the ERCC2 gene result in different defective DNA repair clinical phenotypes, with variable onset and severity, including Xeroderma pigmentosum type D (XP-D, OMIM #278730), 2 Trichothiodystrophy (TTD; OMIM #601675), and Cerebro-oculo-facioskeletal syndrome 2 (COFS2; OMIM #610756). 3 Here, we report on a 2-year-old female patient with bi-allelic ERCC2 pathogenic variants showing clinical features different from those generally reported in ERCC2 mutated patients, including mild prenatal and severe postnatal growth deficiency and microcephaly, who developed a pilocytic astrocytoma of the brainstem.…”

Early‐onset nucleotide excision repair disorders with neurological impairment: Clues for early diagnosis and prognostic counseling

“…Nucleotide excision repair (NER) is a multistep DNA repair mechanism involved in the removal of single-strand DNA damages induced by ultraviolet light. 1 Besides participating to this repair pathway, proteins implicated in NER are also involved in other DNA repair mechanisms and in DNAassociated processes such as transcription and chromatin architecture. [2][3][4] Genetic defects in NER lead to a broad variety of autosomal recessive overlapping diseases, namely Cerebro-Oculo-Facio-Skeletal syndrome (COFS), Cockayne syndrome (CS), Xeroderma Pigmentosum (XP), Trichothiodystrophy (TTD), and UV-sensitive syndrome (UVSS).…”

“…Twelve NER genes have been associated to five distinct disorders (CS, XP, COFS, TTD and UVSS) and overlapping phenotypes such as XP-CS. 1 AMong these genes, some of them are mostly implicated in early subtypes of NER-related diseases: ERCC2/ XPD, ERCC3/XPB, ERCC5/XPG, ERCC6/CSB and ERCC8/CSA. Pathogenic variants in ERCC1 have been reported in rare COFS patients.…”