Molecular genetic analysis of 16 XP-C patients from Germany: environmental factors predominately contribute to phenotype variations Annika Scha ¨ fer 1 , Lars Hofmann 1 , Alexei Gratchev 2 , Petra Laspe 1 , Steffen Schubert 1 , Anke Schu ¨ rer 1 , Andreas Ohlenbusch 3 , Mladen Tzvetkov 4 , Christian Hallermann 5 , Jo ¨ rg Reichrath 6 , Michael P. Scho ¨n 1 and Steffen Emmert 1 1 Department of Dermatology, Venerology and Allergology, University Medical Center Go ¨ttingen, Go ¨ttingen, Germany; 2 Department of Dermatology, Venerology, and Allergology, University Medical Center Mannheim, Mannheim, Germany; 3 Department of Pediatrics, University Medical Center Go ¨ttingen, Go ¨ttingen, Germany; 4 Department of Clinical Pharmacology, University Medical Center Go ¨ttingen, Go ¨ttingen, Germany; 5 Department of Dermatology, Fachklinik Hornheide, Mu ¨nster, Germany; 6 Department of Dermatology, Venereology, and Allergology, University Clinic Saarland, Homburg, Germany Correspondence: Steffen Emmert, Department of Dermatology, Venerology and Allergology, University Medical Center Go ¨ttingen, Robert-Koch-Str. 40, 37075 Go ¨ttingen, Germany, Tel.: +49551-396410, Fax: +49551-398983, e-mail: semmert@gwdg.de Abstract: Patients belonging to xeroderma pigmentosum (XP) complementation group C comprise one-third of all XP patients. Only four major reports compiled larger groups of XP-C patients from southern Europe (12 pts), North America (16 pts) and Africa (14 and 56 pts) as well as their genetic background (46 XPC mutations). We identified 16 XP-C patients from Germany. Interestingly, only five patients exhibited severe sun sensitivity. The mean age of XP diagnosis was 9.4 years, and the median age of the first skin cancer was 7 years. Neurological symptoms were absent in all but two patients. Primary fibroblasts from all 16 patients showed reduced post-UV cell survival (mean: 50% vs 93% in normal cells) and reduced reactivation of an UV-treated luciferase reporter gene (mean: 6.4% vs 30.7% in normal cells). XPC mRNA expression was also greatly reduced compared with normal cells (mean: 14.3%; range 8.3–25.7%) except in XP47MA (274.1%). All patients carried homozygous XPC mutations. Four mutations have been described previously: c.1747_1748delTG (found in 4/16), c.567 C>T (4/16), c.1839 C>T (1/16) and a complex insertion/deletion mutation in exon 9 (1/16). The novel frameshift mutations c.446_447delAG (2/16), c.1525insA (1/16) and c.2271delC (1/16) lead to truncated XPC proteins as does the novel nonsense mutation c.843C>T (1/16). XP47MA carries an interesting mutation (c.2538_2540delATC; p.Ile812del) resulting in an in-frame single amino acid deletion. This mutation results in a classical XP phenotype, a non-functional XPC protein, but elevated XPC mRNA expression. Our study indicates that extrinsic factors may contribute to XP-C symptom severity due to nonsense-mediated message decay. Key words: nucleotide excision repair – skin cancer – ultraviolet radiation – xeroderma pigmentosum – XPC Accepted for publication 18 October 2012 Introduction Xeroderma pigmentosum (XP) is a rare autosomal recessively inherited disorder caused by a defect in the nucleotide exci- sion repair (NER) pathway. The hallmarks of XP include increased sun sensitivity since birth as well as freckling, hyper- and hypopigmentations, skin atrophy and premature skin age- ing within sun-exposed skin starting as early as 2–3 years of age. Interestingly, about one-third of the XP patients do not exhibit any sun sensitivity. Eventually, development of non- melanoma (~10,000-fold increased risk) as well as melanoma skin cancer (~2000-fold increased risk) occurs in XP patients starting at a median age of about 9 and 22 years, respectively (1–3). Tumors are preferentially located on sun-exposed areas. About 25% of XP patients also exhibit progressive neurological degeneration with features of premature ageing in addition to their XP symptoms. To date, seven XP genes involved in the NER pathway, XPA to XPG, have been identified. Accordingly, XP patients can be assigned to seven complementation groups, XP-A to XP-G, depending on the mutated gene. In addition, a XP variant form exists which is caused by mutations in the gene coding for DNA polymerase eta whose gene product allows for error-free transle- sional synthesis, for example across UV photoproducts (4). XP occurs worldwide. In North America, the incidence is estimated at 1/1,000,000 inhabitants. In Japan, XP-A patients and several XPA founder mutations prevail due to the isolated island location. The incidence in North Africa and the Middle East is much higher due to common consanguinity (1/50,000). The inci- dence for XP in Western Europe was recently assessed as 2.3/ 1,000,000 inhabitants (5). The nucleotide excision repair (NER) pathway can be divided into the slow global genome repair (GGR) and the rapid tran- scription-coupled repair (TCR) subpathways. The predominant difference between GGR and TCR is the damage recognition step. While TCR is initiated by stalled RNA polymerases at photo lesions on the transcribed DNA strand, the initial damage recogni- tion in GGR is performed by XPC in complex with HR23B and Centrin-2 together with XPE (DDB2) (6–9). The XP complementation group C (MIM #278720) is the most frequent complementation group in the United States and Europe (25–40% of all XP patients), especially in the Mediterranean coun- tries of southern Europe and Northern Africa (10,11). As XPC is 24 ª 2012 John Wiley & Sons A/S Experimental Dermatology, 2013, 22, 24–29 DOI: 10.1111/exd.12052 www.blackwellpublishing.com/EXD Original Article