A Novel Complex Insertion/Deletion Mutation in the XPC DNA Repair Gene Leads to Skin Cancer in an Iraqi Family Steffen Emmert, Tino Wetzig, Kyoko Imoto,

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A Novel Complex Insertion/Deletion Mutation in the XPC DNA Repair Gene Leads to Skin Cancer in an Iraqi Family Steffen Emmert, Tino Wetzig, Kyoko Imoto, Sikandar G. Khan, Kyu-Seon Oh, Petra Laspe, Karolin Zachmann, Jan C. Simon, Kenneth H. Kraemer Journal of Investigative Dermatology Volume 126, Issue 11, Pages 2542-2544 (November 2006) DOI: 10.1038/sj.jid.5700452 Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Pedigree, clinical picture, reduced post-UV cell survival, and complementation group assignment of XP5GO and XP6GO. (a) Pedigree of the Iraqi family. (b) Detailed view of the face of 10-year-old XP patient, XP6GO. Hyper- as well as hypopigmentation and dry skin is visible. The skin shows evidence of severe premature photodamage. Cheilitis of both lips indicates severe sun damage. Arrow: basal cell carcinoma. (c) Reduced cell survival of XP5GO and XP6GO fibroblasts compared to normal control fibroblasts (obtained from a skin biopsy from a healthy boy; not exactly age-matched) after irradiation with an increasing UVC dose. UVC source: CL-100 (LTF Labortechnik, Wasserburg, Germany). Error bars: mean±SD (n=2). (d) Reduced luciferase expression in XP5GO and XP6GO fibroblasts that is complemented by XPC cDNA in a host cell reactivation (HCR) assay. The HCR assay measures the ability of the host cells to repair UV-damaged plasmid DNA by assessing the recovery of a reporter gene expression, measured indirectly as enzyme activity of the luciferase reporter gene. The amount of luciferase expression represents the cellular repair capacity for UV-induced DNA photoproducts. Relative luciferase activities (percentage of 1,000J/m2 UVC-irradiated vs unirradiated pCMVLuc plasmid) are depicted (mean±SD; n=3). UVC source: CL-1000 (LTF Labortechnik, Germany). Journal of Investigative Dermatology 2006 126, 2542-2544DOI: (10.1038/sj.jid.5700452) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 XPC mRNA expression analysis, XPC protein expression analysis, and XPC sequence analysis. (a) Reduced XPC mRNA expression in XP5GO and XP6GO cells was measured using real-time quantitative reverse transcriptase-PCR and SYBR Green (DNA intercalating agent) employing exon 12 spanning primers as described (Khan et al., 2002). (b) XPC protein levels in fibroblasts from a normal control (AG13145; lane 1), a known XPC patient (XP16VI; lane 2), the Iraqi girl (XP5GO; lane 3), and the Iraqi boy (XP6GO; lane 4) as assessed by Western blotting. The β-actin protein expression was measured as an internal control. Relative band intensities (percentage XPC vs actin) are depicted. (c) Sequence analysis of the XPC gene revealing a homozygous insertion/deletion mutation within XPC exon 9 in XP5GO and XP6GO genomic DNA (Genbank database accession number AF261899). Twelve bases are deleted from the wild-type sequence and replaced by 25 new bases. Homologies between the inserted bases and the reverse wild-type sequence are indicated. Journal of Investigative Dermatology 2006 126, 2542-2544DOI: (10.1038/sj.jid.5700452) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions