1. ¹DNA Repair Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
2. ²Ankara Ataturk Research and Training Hospital, Dermatology Clinic, Ankara, Turkey
3. ³Department of Medical Biology and Genetics, Yeditepe University Medical School, Istanbul, Turkey
4. ⁴Department of Dermatology, Georg-August-University, Goettingen, Germany
5. ⁵Department of Human Genetics, Tel Aviv University School of Medicine, Tel Aviv, Israel
6. ⁶Armed Forces Institute of Pathology, Washington, District of Columbia, USA
7. ⁷NIAMS Extramural Program, Bethesda, Maryland, USA
8. ⁸Division of Dermatopharmacology, Department of Dermatology, The Warren Alpert School of Medicine of Brown University, Providence, Rhode Island, USA
9. ⁹Department of Dermatology, University of Wuerzburg, Wuerzburg, Germany
10. ¹⁰Department of Dermatology, University Medical Center Mannheim, Ruprecht–Karls University of Heidelberg, Mannheim, Germany
11. ¹¹Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
12. ¹²Department of Dermatology, Tel Aviv University School of Medicine, Tel Aviv, Israel
13. ¹³Laboratory of Genomic Integrity, National Institute of Child Health and Human Development, Bethesda, Maryland, USA
14. ¹⁴Nanobiology Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA

Correspondence: Dr Kenneth H. Kraemer, DNA Repair Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Building 37, Room 4002 MSC 4258, Bethesda, Maryland 20892-4258, USA. E-mail: kraemerk@nih.gov

¹⁵These authors contributed equally to this work

Deceased.

Received 5 December 2007; Revised 24 January 2008; Accepted 25 January 2008; Published online 27 March 2008.

Abstract

Xeroderma pigmentosum-variant (XP-V) patients have sun sensitivity and increased skin cancer risk. Their cells have normal nucleotide excision repair, but have defects in the POLH gene encoding an error-prone polymerase, DNA polymerase (pol). To survey the molecular basis of XP-V worldwide, we measured pol protein in skin fibroblasts from putative XP-V patients (aged 8–66 years) from 10 families in North America, Turkey, Israel, Germany, and Korea. Pol was undetectable in cells from patients in eight families, whereas two showed faint bands. DNA sequencing identified 10 different POLH mutations. There were two splicing, one nonsense, five frameshift (3 deletion and 2 insertion), and two missense mutations. Nine of these mutations involved the catalytic domain. Although affected siblings had similar clinical features, the relation between the clinical features and the mutations was not clear. POLH mRNA levels were normal or reduced by 50% in three cell strains with undetectable levels of pol protein, indicating that nonsense-mediated message decay was limited. We found a wide spectrum of mutations in the POLH gene among XP-V patients in different countries, suggesting that many of these mutations arose independently.