Two New XPD Patients Compound Heterozygous for the Same Mutation Demonstrate Diverse Clinical Features Mitsuo Fujimoto, Suzanne N. Leech, Therina Theron,

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Two New XPD Patients Compound Heterozygous for the Same Mutation Demonstrate Diverse Clinical Features Mitsuo Fujimoto, Suzanne N. Leech, Therina Theron, Masato Mori, Heather Fawcett, Elena Botta, Yasuyuki Nozaki, Takanori Yamagata, Shin-Ichi Moriwaki, Miria Stefanini, Mariko Y. Momoi, Hidemi Nakagawa, Sam Shuster, Celia Moss, Alan R. Lehmann Journal of Investigative Dermatology Volume 125, Issue 1, Pages 86-92 (July 2005) DOI: 10.1111/j.0022-202X.2005.23745.x Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical features of patient 1 (XP1JI). (a) Bilateral rocker-bottom feet. (b) Computed tomography head showing basal ganglia calcification. (c) Patient 1(XP1J1) face showing increased freckling. (d) Large squamous cell carcinoma over left eye. XP, xeroderma pigmentosum. Journal of Investigative Dermatology 2005 125, 86-92DOI: (10.1111/j.0022-202X.2005.23745.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Clinical features of patient 2 (XPINE). (a) Patient 2 (XP1NE) face showing freckling, hyperpigmentation and actinic keratoses, beaking of nose, and shrunken eyes. (b) Freckling of sun exposedhands with sclerodactyly changes affecting fingers. XP, xeroderma pigmentosum. Journal of Investigative Dermatology 2005 125, 86-92DOI: (10.1111/j.0022-202X.2005.23745.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Cellular responses of XP1JI to ultraviolet (UV) C. (a) UV survival. Normal or XP1JI cells were UV irradiated and plated to form colonies after suitable dilution. Data for XP1NE and XP8BR are taken from Taylor et al (1997) andBroughton et al (2001). (b) RNA synthesis. Serum-starved cells were UV irradiated with the indicated doses, incubated for 24 h, and then labelled with 3H-uridine to measure RNA synthesis. Means±SEM of two to four experiments are shown including XP1DU from an xeroderma pigmentosum (XP) complementation group D (XPD) patient with xeroderma pigmentosum (XP). (c) Unscheduled DNA synthesis (UDS). Serum-starved cells were UV irradiated, and incubated for 2 h in the presence of hydroxyurea and 3H-thymidine to measure the amount of repair synthesis. 48BR and SF are normal cells. (d) Complementation analysis. Cells were cotransfected with the UV irradiated chloramphenicol acetyltranferase (CAT) plasmid together with pcDNA3 containing the indicated cDNA. After incubation for 48 h, the CAT activity was measured. Journal of Investigative Dermatology 2005 125, 86-92DOI: (10.1111/j.0022-202X.2005.23745.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Mutation analysis and cellular responses. (a) Mutation analysis: genomic DNA from XP1J1 and parents were amplified by PCR using primers spanning the G47R mutation site. The PCR products were incubated either without (lanes marked-) or with MvaI (lanes marked+) and electrophoresed on an agarose gel. Lane 1: marker; lanes 2 and 3: control (normal fibroblast genomic DNA), lanes 4 and 5: proband; lanes 6 and 7: father; lanes 8 and 9: mother; lane 10: marker. (b) Breaks generated in cellular DNA. Cells embedded in agarose were irradiated with the indicated doses of ultraviolet B and then incubated for 1 h in the presence of hydroxyurea and ara-C. The length of the comet tail moment was determined after lysis, electrophoresis, and staining with ethidium bromide. (c) TFIIH levels: Steady-state levels of TFIIEα (white columns) and of the cdk7 (dotted columns), p44 (dashed columns), and p62 (black columns) subunits of TFIIH are expressed as percentages of the amounts present in the healthy individual C3PV analyzed in parallel. Means of two experiments are shown. XP, xeroderma pigmentosum. Journal of Investigative Dermatology 2005 125, 86-92DOI: (10.1111/j.0022-202X.2005.23745.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions