Disorders of nucleotide excision repair

Xeroderma pigmentosum [DS:H01428]
Cockayne syndrome [DS:H00076]
UV-sensitive syndrome [DS:H02131]
Trichothiodystrophy [DS:H00866]
Cerebro-oculo-facio-skeletal syndrome
XFE progeroid syndrome

Mutations in genes on the nucleotide excision repair pathway are associated with diseases, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). XP is caused by mutations in XPA, ERCC3/XPB, XPC, ERCC2/XPD, DDB2/XPE, ERCC4/XPF, ERCC5/XPG and POLH. XP is classified into eight genetic complementation groups by the present. In this inside, 7groups from the XP-A group to the G group show the abnormality in NER. The symptoms of XP begin in early life. Severe sunburn and blistering occurs in a half of patients, and all show early extensive freckling. Cancer incidence for individuals with XP under 20 years of age is 2,000 times as high as incidence in the general population. Neurodegeneration can be correlated with mutations in specific XP genes (XPA, ERCC3, ERCC2 and ERCC5). Some patients of XP- A develop neurologic symptoms or a more severe clinical phenotype known as de Sanctis-Cacchione syndrome, associated with mutations in the ERCC6 gene. CS is caused by mutations in ERCC8/CSA, ERCC6/CSB. CS is predominantly a developmental and neurological disorder. It results in a severely reduced lifespan but is not linked to an increased incidence of cancer. The three of the XP genes (ERCC2, ERCC3, and ERCC5) are also found to be mutated XP/CS patients (exhibiting both XP and Cockayne's symptoms). ERCC6 is a cause of UV-sensitive syndrome (UVS) which is characterized by photosensitivity and mild freckling but without neurological abnormalities or skin tumors. TTD is a premature aging syndrome, with the hallmark feature of brittle hair and nails, ichthyosis, and progressive mental and physical retardation. Within photo-sensitive TTD, three TFIIH coding genes (ERCC2, ERCC3, and TTDA/GTF2H5) are implicated. Cerebro-oculo-facio-skeletal (COFS) syndrome is rare autosomal recessive disorder with microcephaly, severe mental retardation, and death in childhood. COFS can result from mutations in ERCC1, ERCC2, ERCC5 and ERCC6.

Congenital malformation

(XPA) XPA; xeroderma pigmentosum, complementation group A [HSA:7507] [KO:K10847]
(XPB, XP/CS, TTD) ERCC3; DNA excision repair protein ERCC-3 [HSA:2071] [KO:K10843]
(XPC) XPC; xeroderma pigmentosum, complementation group C [HSA:7508] [KO:K10838]
(XPD, XP/CS, TTD) ERCC2; DNA excision repair protein ERCC-2 [HSA:2068] [KO:K10844]
(XPE) DDB2; damage-specific DNA binding protein 2 [HSA:1643] [KO:K10140]
(XPE-2) DDB1; damage-specific DNA binding protein 1 [HSA:1642] [KO:K10610]
(XPF) ERCC4; DNA excision repair protein ERCC-4 [HSA:2072] [KO:K10848]
(XPG, XP/CS, COFS3) ERCC5; DNA excision repair protein ERCC-5 [HSA:2073] [KO:K10846]
(XPV) POLH; DNA polymerase eta [HSA:5429] [KO:K03509]
(CSA) ERCC8; DNA excision repair protein ERCC-8 [HSA:1161] [KO:K10570]
(CSB, DSC, UVS, COFS1) ERCC6; DNA excision repair protein ERCC-6 [HSA:2074] [KO:K10841]
(TTD) GTF2H5; general transcription factor IIH, polypeptide 5 [HSA:404672] [KO:K10845]
(COFS4) ERCC1; DNA excision repair protein ERCC-1 [HSA:2067] [KO:K10849]

Disorder of DNA repair system

PMID:19809470

Cleaver JE, Lam ET, Revet I

Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity.

Nat Rev Genet 10:756-68 (2009)
DOI:10.1038/nrg2663

PMID:11710928 (XP and TTD)

Queille S, Drougard C, Sarasin A, Daya-Grosjean L

Effects of XPD mutations on ultraviolet-induced apoptosis in relation to skin cancer-proneness in repair-deficient syndromes.

J Invest Dermatol 117:1162-70 (2001)
DOI:10.1046/j.0022-202x.2001.01533.x

PMID:11443545 (COFS)

Graham JM Jr, Anyane-Yeboa K, Raams A, Appeldoorn E, Kleijer WJ, Garritsen VH, Busch D, Edersheim TG, Jaspers NG

Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy.

Am J Hum Genet 69:291-300 (2001)
DOI:10.1086/321295

PMID:15220921 (TTD)

Giglia-Mari G, Coin F, Ranish JA, Hoogstraten D, Theil A, Wijgers N, Jaspers NG, Raams A, Argentini M, van der Spek PJ, Botta E, Stefanini M, Egly JM, Aebersold R, Hoeijmakers JH, Vermeulen W

A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A.

Nat Genet 36:714-9 (2004)
DOI:10.1038/ng1387

PMID:18339586 (TTD and CS)

Brooks PJ, Cheng TF, Cooper L

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

DNA Repair (Amst) 7:834-48 (2008)
DOI:10.1016/j.dnarep.2008.01.017

PMID:20221251 (XFE progeroid syndrome)

Ahmad A, Enzlin JH, Bhagwat NR, Wijgers N, Raams A, Appledoorn E, Theil AF, J Hoeijmakers JH, Vermeulen W, J Jaspers NG, Scharer OD, Niedernhofer LJ

Mislocalization of XPF-ERCC1 nuclease contributes to reduced DNA repair in XP-F patients.

PLoS Genet 6:e1000871 (2010)
DOI:10.1371/journal.pgen.1000871