title: A new XPC gene splicing mutation has lead to the highest worldwide prevalence of xeroderma pigmentosum in black Mahori patients.
abstract: Xeroderma pigmentosum (XP) is a rare, recessive disease characterized by sunlight hypersensitivity and early appearance of cutaneous and ocular malignancies. We report the first description of a very high incidence (around 1/5000) of black XP patients in the Mayotte population in the Indian Ocean. Among a cohort of 32 XP, we describe the clinical and genetic features of 18 living Comorian black XP patients. We discuss the remarkable clinical differences between white and black XPs. Skin and ocular abnormalities are remarkably precocious and severe XP phenotypes are recognized by the early ocular injuries. In our cohort, the first skin cancer appeared at a median age of 4.5 years with no neurological symptoms. Post-UV DNA repair, cell survival and genetic complementation assigned these patients to the XP group C. All patients exhibited a new G→C homozygous substitution at 3'-end of XPC intron 12 (IVS 12-1G>C) leading to the abolition of an acceptor splicing site and the absence of the XPC protein. We found 3 different mRNA isoforms: one with retention of intron 12, one showing exon 13 skipping, and a third with a 44bp deletion in exon 13. These 3 isoforms were differently expressed in XP-C cells compared to normal cells. This new mutation found in the Comorian islands, where consanguinity is frequent, represents a founder effect, with an estimated age of about 770 years. Due to the African origin of the black XPs from Mayotte, it would be valuable to search for this mutation in African XPs whenever possible.
authors.affiliation: Department of Medical Genetics, INSERM U781 CHR Félix Guyon, La Réunion, and CHU Necker, Paris, France. francois.cartault@chr-reunion.fr
authors.forename: François
authors.initials: F
authors.lastname: Cartault
authors.forename: Caroline
authors.initials: C
authors.lastname: Nava
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Malbrunot
authors.forename: Patrick
authors.initials: P
authors.lastname: Munier
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Hebert
authors.forename: Patrick
authors.initials: P
authors.lastname: N'guyen
authors.forename: Nadia
authors.initials: N
authors.lastname: Djeridi
authors.forename: Philippe
authors.initials: P
authors.lastname: Pariaud
authors.forename: Joelle
authors.initials: J
authors.lastname: Pariaud
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dupuy
authors.forename: Frédéric
authors.initials: F
authors.lastname: Austerlitz
authors.forename: Alain
authors.initials: A
authors.lastname: Sarasin
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017507:Comoros / Q000453:epidemiology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D014983:Xeroderma Pigmentosum / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C086984:XPC protein, human