Photochemistry and Photobiology, 2015, 91: 484–485
Research Note Xeroderma Pigmentosum in the United Kingdom† Alan R. Lehmann* Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK Received 11 March 2014, accepted 12 June 2014, DOI: 10.1111/php.12301
ABSTRACT
exclude the diagnosis of XP in several hundred patients from various countries. Other laboratories, including those in NIH (Ken Kraemer), Rotterdam, Netherlands (Koos Jaspers), Villejuif, France (Alain Sarasin) and Pavia, Italy (Miria Stefanini) have of course established similar services, all based on measurement of defective repair synthesis (7). Until about 15 years ago, however, I had not met any XP patients. This all changed when Sandra Webb, the mother of a boy with XP, established an XP support group in the United Kingdom (http://xpsupportgroup.org.uk/) and invited me to attend their annual “Owl patrol” weekend camp for XP families. It has been a great privilege to meet them, to hear about their issues and how they deal with them, as well as putting faces to some of the cell lines that we had analyzed in our laboratory over many years. A few years later, Arjida Woollons, a local dermatologist who had spent 2 years working in our institute, had the idea of establishing a specialized XP clinic. This started off on an ad hoc and somewhat haphazard basis, but in 2009 Robert Sarkany, a dermatologist at St Thomas’ Hospital in London, put in an application, with the involvement of myself and Sandra Webb, to the U.K. National Health Service National Commissioning Group for a fully funded XP multidisciplinary specialist clinic that meets every 2 weeks. This application was successful and the clinic was established in April 2010 (http://www.guysandstthomas.nhs.uk/ our-services/dermatology/specialties/xeroderma-pigmentosum/ overview.aspx). In general, four patients spend the whole day at the clinic being examined by dermatologist, neurologist (pediatric or adult), ophthalmologist, psychologist and geneticist and on their first visit I give them a layman’s guide to NER and its deficiency in XP. We now have more than 75 XP patients on our books, which probably represents in excess of 80% of the U.K. XP population. We have representatives of all eight XP complementation groups, with groups A, C, D and variant being the most preponderant. Patients typically attend once a year, but more frequently if necessary. Any potentially dangerous skin lesions are removed immediately. Crucial to the service are the XP specialist nurses, who visit the families in their homes and assist with any problems in adapting their homes for solar protection, dealing with social services etc. (8). Before we established the clinic, I thought I knew pretty much everything there was to know about XP, but I have learnt from seeing patients in the clinic that I knew almost nothing. Only one of our patients looks like a textbook case, we are constantly astounded by the heterogeneity, much but not all of which can be accounted for by the precise genotype, and many of the published generalizations about XP turn out to be too
The seminal discovery by James Cleaver of defective DNA repair in xeroderma pigmentosum (XP) opened up an everexpanding field of DNA repair-related disorders. In addition, it put XP on the map and has led to improved diagnosis, care and management of affected patients. In the United Kingdom, we recently established a multidisciplinary specialist clinic for XP patients. All XP patients in the United Kingdom are able to visit the clinic where they are examined and advised by a team of specialists with detailed knowledge of the different aspects of XP.
INTRODUCTION In the late 1960s, I was a graduate student at what is now the Institute of Cancer Research, near London, UK, doing my PhD on DNA damage and DNA replication. At some point in the middle of my studies, we were visited by a Brit, working in the USA, named James Cleaver, who gave a seminar on his discovery of defective DNA repair in patients with xeroderma pigmentosum (XP) (1). The dramatic effect of this discovery, doubtless also highlighted in other contributions to this special issue, was that DNA repair, a relatively recently discovered process considered rather abstruse and esoteric, was revealed to be clinically important. In 1971, in my first year as a post doc at Oak Ridge National Laboratories in Tennessee, I visited Jim’s laboratory in San Francisco and he was kind enough, not only to allow me to give a seminar on my work but also to give me a substantial honorarium to go with it. His work on the defect in nucleotide excision repair (NER) in XP led to the discovery by Jay Robbins and colleagues of XP variants with normal NER (2,3), and stimulated me to try and find the defect in XP variants. I was able to show that XP variants were defective in their ability to replicate past UV-damaged DNA (4) and this has been one of my main claims to fame during my research career. More importantly, Jim’s discovery stimulated many researchers to look for other human disorders caused by defects in DNA repair. Over the years this has been spectacularly successful with many such disorders identified (e.g. see Chapters 24–28 in (5), and (6)). As an adjunct to my research work, I established a diagnostic service for XP, based on Jim’s discovery of defective repair replication and over the years this has helped to confirm or *Corresponding author email: [email protected] (Alan R. Lehmann) †This paper is part of the Special Issue honouring James Cleaver. © 2014 The American Society of Photobiology
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Photochemistry and Photobiology, 2015, 91 simple. For example, it has been known for many years that most patients from XP-A, B, D, F and G are likely to have neurological complications, whereas those in groups C, E and V are free of this type of neurodegeneration. However, what is less well known is that patients in the former groups also show acute sun sensitivity, whereas those in the latter group have a completely normal sunburn reaction (9,10). These findings suggest that transcription-coupled NER, which is functional in the latter but not in the former groups, protects the patients not only from neurodegeneration but also from acute sunburn. There is, however, a sting in the tail. Patients who have a severe sunburn reaction are likely to be diagnosed early and protected from sun exposure from an early age. In contrast, those patients that do not have a sunburn reaction cannot be diagnosed until they show other clinical features, such as abnormal freckling and other pigmentation changes. These are not normally manifest until the age of at least 2 years in the general population but in the case of XP-C children may occur at a younger age. Abnormal manifestations are not seen until much later in XP-E and XP-V patients. As a consequence they are likely to be diagnosed later, in some cases much later, by which time they will have accumulated significant UV-induced mutations and are more likely to develop skin cancers. Thus, paradoxically, patients in those groups generally considered to be the more mildly affected groups, are in fact more likely to develop multiple skin cancers (10). Rare patients with the combined features of XP and Cockayne Syndrome (CS) have been reported in XP groups B, D and G. One of our patients had the combined features, not only of XP and CS but also of Fanconi Anemia. Much to our surprise, this patient was assigned to the XP-F group (11). Together with the group of Tomoo Ogi in Japan, we also identified mutations in the XPF gene in a Cockayne Syndrome patient from the USA. Remarkably, both these patients had the identical mutation in one allele of the XPF gene, resulting in the alteration of cysteine-236 to arginine in the XPF protein (11). At the same time Bogliolo and coworkers reported two Fanconi Anemia patients with mutations in the XPF gene (12). It thus appears that mutations in the XPF gene can result in clinical phenotypes that are as complex and diverse as those resulting from XPD mutations (13). The published average age of death of XP patients is 32 years (10). We expect that the improved management, care and help that we are now able to provide the patients will result in a substantial increase in lifespan. Indeed, we anticipate that those without neurological complications will have a close-to-normal lifespan. Needless to say, none of this progress would have been possible without Jim Cleaver’s seminal discovery.
485
REFERENCES 1. Cleaver, J. E. (1968) Deficiency in repair replication of DNA in xeroderma pigmentosum. Nature 218, 652–656. 2. Burk, P. G., M. A. Lutzner, D. D. Clarke and J. H. Robbins (1971) Ultraviolet-stimulated thymidine incorporation in xeroderma pigmentosum lymphocytes. J. Lab. Clin. Med. 77, 759–767. 3. Robbins, J. H., K. H. Kraemer, M. A. Lutzner, B. W. Festoff and H. G. Coon (1974) Xeroderma pigmentosum: an inherited disease with sun- sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair. Ann. Intern. Med. 80, 221–248. 4. Lehmann, A. R., S. Kirk-Bell, C. F. Arlett, M. C. Paterson, P. H. M. Lohman, E. A. de Weerd-Kastelein and D. Bootsma (1975) Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV-irradiation. Proc. Natl Acad. Sci. USA 72, 219–223. 5. Friedberg, E. C., G. C. Walker, W. Siede, R. D. Wood, R. A. Schultz and T. Ellenberger (2005) DNA Repair and Mutagenesis, 2nd edn. ASM Press, Washington DC. 6. O’Driscoll, M. (2013) Diseases associated with defective responses to DNA damage. In DNA Repair, Mutagenesis and other Responses to DNA Damage (Edited by E. C. Friedberg, S. J. Elledge, A. R. Lehmann, T. Lindahl and M. Muzi-Falconi), pp. 411–435. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York. 7. Cleaver, J. E. (1969) Xeroderma pigmentosum: a human disease in which an initial stage of DNA repair is defective. Proc. Natl Acad. Sci. USA 63, 428–435. 8. Turner, S., K. Mullard, H. Fassihi and R. Sarkany (2013) Nursing patients with xeroderma pigmentosum in the UK. Dermatol. Nursing 12, 20–26. 9. Sethi, M., A. R. Lehmann, H. Fawcett, M. Stefanini, N. Jaspers, K. Mullard, S. Turner, A. Robson, D. McGibbon, R. Sarkany and H. Fassihi (2013) Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions. Br. J. Dermatol. 169, 1279–1287. 10. Bradford, P. T., A. M. Goldstein, D. Tamura, S. G. Khan, T. Ueda, J. Boyle, K. S. Oh, K. Imoto, H. Inui, S. I. Moriwaki, S. Emmert, K. M. Pike, A. Raziuddin, T. M. Plona, J. J. Digiovanna, M. A. Tucker and K. H. Kraemer (2011) Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J. Med. Genet. 48, 168–176. 11. Kashiyama, K., Y. Nakazawa, D. T. Pilz, C. Guo, M. Shimada, K. Sasaki, H. Fawcett, J. F. Wing, S. O. Lewin, L. Carr, T. S. Li, K. Yoshiura, A. Utani, A. Hirano, S. Yamashita, D. Greenblatt, T. Nardo, M. Stefanini, D. McGibbon, R. Sarkany, H. Fassihi, Y. Takahashi, Y. Nagayama, N. Mitsutake, A. R. Lehmann and T. Ogi (2013) Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes cockayne syndrome, xeroderma pigmentosum, and fanconi anemia. Am. J. Hum. Genet. 92, 807–819. 12. Bogliolo, M., B. Schuster, C. Stoepker, B. Derkunt, Y. Su, A. Raams, J. P. Trujillo, J. Minguillon, M. J. Ramirez, R. Pujol, J. A. Casado, R. Banos, P. Rio, K. Knies, S. Zuniga, J. Benitez, J. A. Bueren, N. G. Jaspers, O. D. Scharer, J. P. de Winter, D. Schindler and J. Surralles (2013) Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am. J. Hum. Genet. 92, 800–806. 13. Lehmann, A. R. (2001) The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev. 15, 15–23.
Research Note Xeroderma Pigmentosum in the United Kingdom† Alan R. Lehmann* Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK Received 11 March 2014, accepted 12 June 2014, DOI: 10.1111/php.12301
ABSTRACT
exclude the diagnosis of XP in several hundred patients from various countries. Other laboratories, including those in NIH (Ken Kraemer), Rotterdam, Netherlands (Koos Jaspers), Villejuif, France (Alain Sarasin) and Pavia, Italy (Miria Stefanini) have of course established similar services, all based on measurement of defective repair synthesis (7). Until about 15 years ago, however, I had not met any XP patients. This all changed when Sandra Webb, the mother of a boy with XP, established an XP support group in the United Kingdom (http://xpsupportgroup.org.uk/) and invited me to attend their annual “Owl patrol” weekend camp for XP families. It has been a great privilege to meet them, to hear about their issues and how they deal with them, as well as putting faces to some of the cell lines that we had analyzed in our laboratory over many years. A few years later, Arjida Woollons, a local dermatologist who had spent 2 years working in our institute, had the idea of establishing a specialized XP clinic. This started off on an ad hoc and somewhat haphazard basis, but in 2009 Robert Sarkany, a dermatologist at St Thomas’ Hospital in London, put in an application, with the involvement of myself and Sandra Webb, to the U.K. National Health Service National Commissioning Group for a fully funded XP multidisciplinary specialist clinic that meets every 2 weeks. This application was successful and the clinic was established in April 2010 (http://www.guysandstthomas.nhs.uk/ our-services/dermatology/specialties/xeroderma-pigmentosum/ overview.aspx). In general, four patients spend the whole day at the clinic being examined by dermatologist, neurologist (pediatric or adult), ophthalmologist, psychologist and geneticist and on their first visit I give them a layman’s guide to NER and its deficiency in XP. We now have more than 75 XP patients on our books, which probably represents in excess of 80% of the U.K. XP population. We have representatives of all eight XP complementation groups, with groups A, C, D and variant being the most preponderant. Patients typically attend once a year, but more frequently if necessary. Any potentially dangerous skin lesions are removed immediately. Crucial to the service are the XP specialist nurses, who visit the families in their homes and assist with any problems in adapting their homes for solar protection, dealing with social services etc. (8). Before we established the clinic, I thought I knew pretty much everything there was to know about XP, but I have learnt from seeing patients in the clinic that I knew almost nothing. Only one of our patients looks like a textbook case, we are constantly astounded by the heterogeneity, much but not all of which can be accounted for by the precise genotype, and many of the published generalizations about XP turn out to be too
The seminal discovery by James Cleaver of defective DNA repair in xeroderma pigmentosum (XP) opened up an everexpanding field of DNA repair-related disorders. In addition, it put XP on the map and has led to improved diagnosis, care and management of affected patients. In the United Kingdom, we recently established a multidisciplinary specialist clinic for XP patients. All XP patients in the United Kingdom are able to visit the clinic where they are examined and advised by a team of specialists with detailed knowledge of the different aspects of XP.
INTRODUCTION In the late 1960s, I was a graduate student at what is now the Institute of Cancer Research, near London, UK, doing my PhD on DNA damage and DNA replication. At some point in the middle of my studies, we were visited by a Brit, working in the USA, named James Cleaver, who gave a seminar on his discovery of defective DNA repair in patients with xeroderma pigmentosum (XP) (1). The dramatic effect of this discovery, doubtless also highlighted in other contributions to this special issue, was that DNA repair, a relatively recently discovered process considered rather abstruse and esoteric, was revealed to be clinically important. In 1971, in my first year as a post doc at Oak Ridge National Laboratories in Tennessee, I visited Jim’s laboratory in San Francisco and he was kind enough, not only to allow me to give a seminar on my work but also to give me a substantial honorarium to go with it. His work on the defect in nucleotide excision repair (NER) in XP led to the discovery by Jay Robbins and colleagues of XP variants with normal NER (2,3), and stimulated me to try and find the defect in XP variants. I was able to show that XP variants were defective in their ability to replicate past UV-damaged DNA (4) and this has been one of my main claims to fame during my research career. More importantly, Jim’s discovery stimulated many researchers to look for other human disorders caused by defects in DNA repair. Over the years this has been spectacularly successful with many such disorders identified (e.g. see Chapters 24–28 in (5), and (6)). As an adjunct to my research work, I established a diagnostic service for XP, based on Jim’s discovery of defective repair replication and over the years this has helped to confirm or *Corresponding author email: [email protected] (Alan R. Lehmann) †This paper is part of the Special Issue honouring James Cleaver. © 2014 The American Society of Photobiology
484
Photochemistry and Photobiology, 2015, 91 simple. For example, it has been known for many years that most patients from XP-A, B, D, F and G are likely to have neurological complications, whereas those in groups C, E and V are free of this type of neurodegeneration. However, what is less well known is that patients in the former groups also show acute sun sensitivity, whereas those in the latter group have a completely normal sunburn reaction (9,10). These findings suggest that transcription-coupled NER, which is functional in the latter but not in the former groups, protects the patients not only from neurodegeneration but also from acute sunburn. There is, however, a sting in the tail. Patients who have a severe sunburn reaction are likely to be diagnosed early and protected from sun exposure from an early age. In contrast, those patients that do not have a sunburn reaction cannot be diagnosed until they show other clinical features, such as abnormal freckling and other pigmentation changes. These are not normally manifest until the age of at least 2 years in the general population but in the case of XP-C children may occur at a younger age. Abnormal manifestations are not seen until much later in XP-E and XP-V patients. As a consequence they are likely to be diagnosed later, in some cases much later, by which time they will have accumulated significant UV-induced mutations and are more likely to develop skin cancers. Thus, paradoxically, patients in those groups generally considered to be the more mildly affected groups, are in fact more likely to develop multiple skin cancers (10). Rare patients with the combined features of XP and Cockayne Syndrome (CS) have been reported in XP groups B, D and G. One of our patients had the combined features, not only of XP and CS but also of Fanconi Anemia. Much to our surprise, this patient was assigned to the XP-F group (11). Together with the group of Tomoo Ogi in Japan, we also identified mutations in the XPF gene in a Cockayne Syndrome patient from the USA. Remarkably, both these patients had the identical mutation in one allele of the XPF gene, resulting in the alteration of cysteine-236 to arginine in the XPF protein (11). At the same time Bogliolo and coworkers reported two Fanconi Anemia patients with mutations in the XPF gene (12). It thus appears that mutations in the XPF gene can result in clinical phenotypes that are as complex and diverse as those resulting from XPD mutations (13). The published average age of death of XP patients is 32 years (10). We expect that the improved management, care and help that we are now able to provide the patients will result in a substantial increase in lifespan. Indeed, we anticipate that those without neurological complications will have a close-to-normal lifespan. Needless to say, none of this progress would have been possible without Jim Cleaver’s seminal discovery.
485
REFERENCES 1. Cleaver, J. E. (1968) Deficiency in repair replication of DNA in xeroderma pigmentosum. Nature 218, 652–656. 2. Burk, P. G., M. A. Lutzner, D. D. Clarke and J. H. Robbins (1971) Ultraviolet-stimulated thymidine incorporation in xeroderma pigmentosum lymphocytes. J. Lab. Clin. Med. 77, 759–767. 3. Robbins, J. H., K. H. Kraemer, M. A. Lutzner, B. W. Festoff and H. G. Coon (1974) Xeroderma pigmentosum: an inherited disease with sun- sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair. Ann. Intern. Med. 80, 221–248. 4. Lehmann, A. R., S. Kirk-Bell, C. F. Arlett, M. C. Paterson, P. H. M. Lohman, E. A. de Weerd-Kastelein and D. Bootsma (1975) Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV-irradiation. Proc. Natl Acad. Sci. USA 72, 219–223. 5. Friedberg, E. C., G. C. Walker, W. Siede, R. D. Wood, R. A. Schultz and T. Ellenberger (2005) DNA Repair and Mutagenesis, 2nd edn. ASM Press, Washington DC. 6. O’Driscoll, M. (2013) Diseases associated with defective responses to DNA damage. In DNA Repair, Mutagenesis and other Responses to DNA Damage (Edited by E. C. Friedberg, S. J. Elledge, A. R. Lehmann, T. Lindahl and M. Muzi-Falconi), pp. 411–435. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York. 7. Cleaver, J. E. (1969) Xeroderma pigmentosum: a human disease in which an initial stage of DNA repair is defective. Proc. Natl Acad. Sci. USA 63, 428–435. 8. Turner, S., K. Mullard, H. Fassihi and R. Sarkany (2013) Nursing patients with xeroderma pigmentosum in the UK. Dermatol. Nursing 12, 20–26. 9. Sethi, M., A. R. Lehmann, H. Fawcett, M. Stefanini, N. Jaspers, K. Mullard, S. Turner, A. Robson, D. McGibbon, R. Sarkany and H. Fassihi (2013) Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions. Br. J. Dermatol. 169, 1279–1287. 10. Bradford, P. T., A. M. Goldstein, D. Tamura, S. G. Khan, T. Ueda, J. Boyle, K. S. Oh, K. Imoto, H. Inui, S. I. Moriwaki, S. Emmert, K. M. Pike, A. Raziuddin, T. M. Plona, J. J. Digiovanna, M. A. Tucker and K. H. Kraemer (2011) Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J. Med. Genet. 48, 168–176. 11. Kashiyama, K., Y. Nakazawa, D. T. Pilz, C. Guo, M. Shimada, K. Sasaki, H. Fawcett, J. F. Wing, S. O. Lewin, L. Carr, T. S. Li, K. Yoshiura, A. Utani, A. Hirano, S. Yamashita, D. Greenblatt, T. Nardo, M. Stefanini, D. McGibbon, R. Sarkany, H. Fassihi, Y. Takahashi, Y. Nagayama, N. Mitsutake, A. R. Lehmann and T. Ogi (2013) Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes cockayne syndrome, xeroderma pigmentosum, and fanconi anemia. Am. J. Hum. Genet. 92, 807–819. 12. Bogliolo, M., B. Schuster, C. Stoepker, B. Derkunt, Y. Su, A. Raams, J. P. Trujillo, J. Minguillon, M. J. Ramirez, R. Pujol, J. A. Casado, R. Banos, P. Rio, K. Knies, S. Zuniga, J. Benitez, J. A. Bueren, N. G. Jaspers, O. D. Scharer, J. P. de Winter, D. Schindler and J. Surralles (2013) Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am. J. Hum. Genet. 92, 800–806. 13. Lehmann, A. R. (2001) The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev. 15, 15–23.
