<unk>  has an autosomal recessive pattern of inheritance. One of the most frequent defects in<unk>  is an autosomal recessive genetic defect in which nucleotide excision repair (NER) enzymes are mutated, leading to a reduction in or elimination of NER. If left unchecked, damage caused by ultraviolet light can cause mutations in individual cell's DNA. The causes of the neurological abnormalities are poorly understood and are not connected with exposure to ultraviolet light. The most current theories suggest that oxidative DNA damage is generated during normal metabolism in the central nervous system, and that some types of this damage must be repaired by NER. Since DNA repair is under genetic control, it can mutate. Many genetic disorders such as<unk>  <unk> ; MIM 278700) are caused by mutations in genes that repair damaged DNA.<unk>  affects the mechanism that repairs UV damage in skin cell DNA. Those affected with the autosomal recessive disorder<unk>  are extremely sensitive to UV light produced by the sun and develop pigmented spots, tumors, and skin cancer with minimal exposure. Individuals with<unk>  are about 1,000 times more likely to develop skin cancer than individuals without the disorder. The molecular defects in<unk>  cells result in a greatly elevated induction of mutations in sun-exposed skin of affected individuals. This increased mutation frequency probably accounts for the pigmentation changes and the skin cancers. Examination of mutations in the p53 gene in tumors from<unk>  patients reveal p53 mutations characteristic of UV exposure in the majority of tumors As with all genetic disorders, genetic counseling and psychological support is appropriate for the families to discuss probability of occurrence in future pregnancies, feelings of isolation and concern about career prospects. There is no cure for<unk> . The most common fate for individuals with<unk>  is early death from cancer.<unk>  repair proteins The<unk> A protein acts during NER as a scaffold for assembly of other DNA repair proteins at sites of DNA damage to ensure appropriate excision of the damage. The<unk> B (ERCC3) protein is employed in unwinding the DNA double helix after DNA damage is initially recognized. Mutations in the<unk> B(ERCC3) gene can lead to<unk>  or<unk>  combined with Cockayne syndrome. The<unk> C protein forms a complex with RAD23B protein to form the initial damage recognition factor in global genomic nucleotide excision repair (GG-NER). This complex recognizes a wide variety of damages that thermodynamically destabilize DNA duplexes. The<unk> D (ERCC2) protein, in combination with the<unk> B helicase-containing transcription/repair complex TFIIH, is employed in unwinding the DNA duplex after damage is initially recognized. Mutations in the<unk> D(ERCC2) gene cause a variety of syndromes;<unk> , trichothiodystrophy (TTD), or a combination of<unk>  and Cockayne syndrome <unk> CS). Both trichothiodystrophy and Cockayne syndrome display features of premature aging, suggesting an association between deficient DNA repair and premature aging (see DNA damage theory of aging).<unk> E is a heterodimeric protein composed of two subunits. The larger subunit DDB1 primarily functions as a core component of CUL4A- and CUL4B-based E3 ubiquitin ligase complexes. Substrates that are ubiquitinnated by these complexes include proteins employed in DNA repair. The<unk> F (ERCC4) protein together with the ERCC1 protein forms a complex usually designated ERCC1-XPF. This complex separates the DNA helix for a short distance on either side of the site of damage. It then acts as an endonuclease to incise the damaged DNA strand on the 5’ side of the damaged site. Mutant cells with deficient ERCC1-XPF are not only defective in NER, but also in the repair of double-strand breaks and inter-strand crosslinks. The<unk> G protein is an endonuclease that incises DNA during NER at the 3’ side of the damaged nucleotide. Mutations in the<unk> G (ERCC5) gene can lead to<unk>  alone, or in combination with Cockayne syndrome (CS), or in combination with infantile lethal cerebro-oculo-facio-skeletal syndrome.
Xeroderma pigmentosum
Cockayne syndrome
Iododerma
Erythropoietic protoporphyria
Chyloderma
Trichothiodystrophy
Keratoderma
Poikiloderma