DNA Repair 10 (2011) 577–585 Contents lists available at ScienceDirect DNA Repair journal homepage: www.elsevier.com/locate/dnarepair A new XPC gene splicing mutation has lead to the highest worldwide prevalence of xeroderma pigmentosum in black Mahori patients Franc ¸ ois Cartault a,∗ , Caroline Nava a , Anne-Claire Malbrunot a , Patrick Munier a , Jean-Christophe Hebert b , Patrick N’guyen a , Nadia Djeridi a , Philippe Pariaud c , Joelle Pariaud c , Aurélie Dupuy d , Frédéric Austerlitz e , Alain Sarasin d,f,∗∗ a Department of Medical Genetics, INSERM U781 CHR Félix Guyon, La Réunion, and CHU Necker, Paris, France b Department of Pediatrics, Hospital of Mamoudzou, Mayotte, France c Department of ORL, Hospital of Mamoudzou, Mayotte, France d UMR8200 CNRS, University Paris-Sud and Institut Gustave Roussy, Villejuif, France e Unité Eco-Anthropologie, UMR 7206 CNRS-Muséum d’Histoire naturelle, Université Paris Diderot, 57, rue Cuvier, 75231 Paris, France f Department of Genetics, Institut Gustave Roussy, France article info Article history: Received 3 February 2011 Received in revised form 3 March 2011 Accepted 8 March 2011 Available online 8 April 2011 Keywords: Xeroderma pigmentosum Black skin XPC Splicing mutation Skin cancer Ocular injuries 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 44 bp 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. © 2011 Elsevier B.V. All rights reserved. 1. Introduction Xeroderma pigmentosum (XP) is a rare, recessive disease char- acterized by sunlight hypersensitivity and high incidence of skin cancer, principally carcinoma and melanoma [1,2]. White XP patients have a >1000 fold increased skin cancer risk on UV- exposed sites with a median age for the first cancer at 8 years. The risk factor for melanoma is also very high [3,4]. ∗ Corresponding author at: Department of Medical Genetics, CHR de La Réunion, Site Félix Guyon, 97400 Saint Denis, France. Tel.: +33 2 6290 6400; fax: +33 2 6290 6405. ∗∗ Corresponding author at: UMR8200, PR2, Institut Gustave Roussy, 94805 Ville- juif, France. Tel: +33 1 42 11 63 28; fax: +33 1 42 11 50 08. E-mail addresses: francois.cartault@chr-reunion.fr (F. Cartault), sarasin@igr.fr (A. Sarasin). Classical XP patients have a defect in one of the seven XP genes, XPA to XPG. These genes belong to the nucleotide excision repair (NER) pathway, involved in the removal of bulky DNA lesions such as UV-induced damage. XP is ubiquitous in the world but its frequency and the genes involved vary between countries. The inci- dence is estimated at 1/1,000,000 in the United States and Europe [5], while it is much higher in Japan (1/100,000), North Africa and the Middle East (around 1/50,000) where consanguinity is com- mon. XP-C (MIM ID #278720) patients are the most common XP worldwide (25–40% of all XP cases). XP-C patients exhibit predom- inantly skin damage and early malignancies without neurological deterioration. The XPC gene (MIM ID*613208) is located on chromo- some 3p25, spans 33 kb and contains 16 exons (82–882 bp). The 940 amino acid XPC protein complexed with HHR23B acts during the initial step of NER in lesion recognition. The XPC–HHR23B complex and DDB1/2 complex are involved in genome overall repair. XP seems to be rare in black individuals and to our knowledge neither the frequency, nor the genes involved have been reported 1568-7864/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.dnarep.2011.03.005