Shining a Light on Xeroderma Pigmentosum

Abstract

Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder of DNA repair characterized by sun sensitivity and ultraviolet (UV) induced skin and mucous membrane cancers. Described in 1874 by Moriz Kaposi in Vienna, nearly 100 years later James Cleaver in San Francisco reported defective DNA repair in XP cells. This eventually provided the basis for a mechanistic link between sun exposure, DNA damage, somatic mutations and skin cancer. XP cells were found to have defects in 7 of the proteins of the nucleotide excision repair pathway and in DNA polymerase eta. XP cells are hypersensitive to killing by UV and XP cancers have characteristic “UV signature” mutations. Clinical studies at NIH found a nearly 10,000-fold increase in skin cancer in XP patients under age 20 years demonstrating the substantial importance of DNA repair in cancer prevention in the general population. About 25 % of XP patients have progressive neurological degeneration with progressive loss of neurons, probably from DNA damage induced by oxidative metabolism which kills non-dividing cells in the nervous system. Interestingly, patients with another disorder, trichothiodystrophy have defects in some of the same genes as XP but they have primary developmental abnormalities without an increase in skin cancer.

Clinical utility gene card for: Xeroderma pigmentosum

“…Consequences: frameshifts, protein truncations, and functional relevant amino-acid substitutions. [1][2][3] XPB/ERCC3: eight known disease-causing mutations from five patients. Mutations: 1 (12.5%) C4A transversion, 1 (12.5%) A4C transversion, 1 (12.5%) G4A transition, 3 (37,5%) T4C transitions, 1 (12.5%) deletion (c.807-808delT_T), and 1 (12.5%) insertion (c.1421-1422insA).…”

“…Consequences: functional relevant amino-acid substitutions, frameshifts/protein truncations. [1][2][3] XPG/ERCC5: 25 known disease-causing mutations from 19 patients. Mutations: 12 (48%) transitions, 5 (20%) transversions, and 8 (32%) deletions.…”

“…Carriers of the mutated polymerase eta gene have been mostly identified in Europe and USA. 1,3,[16][17][18][19] 1.9 Diagnostic setting…”

Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum

“…12,13 At the National Institutes of Health (NIH), we have examined XP patients since 1971 and TTD patients since 2001 as part of a natural history protocol. 7,13 Our review of all English-language-published case reports of TTD patients found 112 TTD patients, of whom 55% had abnormal characteristics at birth and 28% had maternal pregnancy complications. 14 We then conducted two molecular epidemiological studies of pregnancy and neonatal abnormalities in mothers of TTD patients in our clinic.…”

“…17 These patients had mutations in at least 8 different genes involved in nucleotide excision repair and polymerase function. 7 In order to determine the influence of the XPD gene, we now have conducted a molecular epidemiological study of pregnancy and neonatal abnormalities in the mothers of the XP patients with XPD mutations in our protocol. We compared these new data to that of the mothers of the TTD patients with XPD mutations from our earlier studies 15,16 and found large differences.…”