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A Distinct Genotype of XP Complementation Group A: Surprisingly Mild Phenotype Highly Prevalent in Northern India/Pakistan/Afghanistan

2015; Elsevier BV; Volume: 136; Issue: 4 Linguagem: Inglês

10.1016/j.jid.2015.12.031

1523-1747

Mieran Sethi, Shaheen Haque, Heather Fawcett, Jonathan Wing, Natalie Chandler, Shehla Mohammed, Ian M. Frayling, P.G. NORRIS, D. McGibbon, Antony R. Young, Robert Sarkany, Alan R. Lehmann, Hiva Fassihi,

Cytomegalovirus and herpesvirus research

Xeroderma pigmentosum (XP) is a rare inherited disorder of DNA repair. Affected individuals cannot repair ultraviolet radiation (UVR)–induced DNA damage, resulting in an increased skin cancer risk (Bradford et al., 2011Bradford P.T. Goldstein A.M. Tamura D. Khan S.G. Ueda T. Boyle J. et al.Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair.J Med Genet. 2011; 48: 168-176Crossref PubMed Scopus (313) Google Scholar), severe sunburn in approximately 50% of patients (Sethi et al., 2013Sethi M. Lehmann A.R. Fawcett H. Stefanini M. Jaspers N. Mullard K. et al.Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions.Br J Dermatol. 2013; 169: 1279-1287Crossref PubMed Scopus (54) Google Scholar), and progressive neurodegeneration in approximately 30% (Kraemer et al., 1987Kraemer K.H. Lee M.M. Scotto J. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases.Arch Dermatol. 1987; 123: 241-250Crossref PubMed Scopus (964) Google Scholar, Totonchy et al., 2013Totonchy M.B. Tamura D. Pantell M.S. Zalewski C. Bradford P.T. Merchant S.N. et al.Auditory analysis of xeroderma pigmentosum 1971-2012: hearing function, sun sensitivity and DNA repair predict neurological degeneration.Brain. 2013; 136: 194-208Crossref PubMed Scopus (37) Google Scholar). XP can result from defects in any of eight genes (XPA–XPG and POLH). XPA–XPG are involved in nucleotide excision repair (NER) of DNA damage (Cleaver et al., 2009Cleaver J.E. Lam E.T. Revet I. Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity.Nat Rev Genet. 2009; 10: 756-768Crossref PubMed Scopus (306) Google Scholar). Xeroderma pigmentosum complementation group A (XP-A) patients usually have a severe phenotype, with exaggerated sunburn and early onset of progressive neurodegeneration, which results in death, usually in the second or third decade (Anttinen et al., 2008Anttinen A. Koulu L. Nikoskelainen E. Portin R. Kurki T. Erkinjuntti M. et al.Neurological symptoms and natural course of xeroderma pigmentosum.Brain. 2008; 131: 1979-1989Crossref PubMed Scopus (94) Google Scholar). XPA protein is required for damage verification in the NER pathway. More than 20 different mutations have been identified in the XPA gene (States et al., 1998States J.C. McDuffie E.R. Myrand S.P. McDowell M. Cleaver J.E. Distribution of mutations in the human xeroderma pigmentosum group A gene and their relationships to the functional regions of the DNA damage recognition protein.Hum Mutat. 1998; 12: 103-113Crossref PubMed Scopus (60) Google Scholar, Takahashi et al., 2010Takahashi Y. Endo Y. Sugiyama Y. Inoue S. Iijima M. Tomita Y. et al.XPA gene mutations resulting in subtle truncation of protein in xeroderma pigmentosum group A patients with mild skin symptoms.J Invest Dermatol. 2010; 130: 2481-2488Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Many of the reported cases come from Japan because of a founder mutation (c.390-1G>C) carried by 1% of the Japanese population (Hirai et al., 2006Hirai Y. Kodama Y. Moriwaki S. Noda A. Cullings H.M. Macphee D.G. et al.Heterozygous individuals bearing a founder mutation in the XPA DNA repair gene comprise nearly 1% of the Japanese population.Mutat Res. 2006; 10: 171-178Crossref Scopus (101) Google Scholar, Satokata et al.,1990Satokata I. Tanaka K. Miura N. Miyamoto I. Satoh Y. Kondo S. et al.Characterization of a splicing mutation in group A xeroderma pigmentosum.Proc Natl Acad Sci U S A. 1990; 87: 9908-9912Crossref PubMed Scopus (97) Google Scholar). This mutation results in abnormal splicing of mRNA and subsequent production of truncated, nonfunctioning XPA protein and the typically severe clinical phenotype. Although a diagnosis of XP-A has usually been associated with a poor prognosis, a number of XP-A patients undergoing long-term follow-up at the UK National XP Clinic have a surprisingly mild phenotype. To examine this finding further, a detailed genotype-phenotype study in this cohort was conducted. Neurological analysis included audiometry, nerve conduction studies, brain magnetic resonance imaging and neuropsychometric evaluations. Informed written consent was obtained from all patients. The study was performed in accordance with protocols approved by the Research Ethics Committee of Guy’s and St. Thomas’ Hospitals NHS Foundation Trust, London (reference 12/LO/0325). Nineteen of 90 patients being studied at the UK National XP clinic were assigned to complementation group A (Table 1). Twelve of these patients, from eight consanguineous families, displayed a mild XP-A phenotype with no ocular surface disease, delayed onset or lack of skin cancer, and normal neurological and neuropsychometric evaluations (Figure 1a–h). Mean age at assessment was 32 years (range 6–79 years) and mean age at clinical diagnosis was 26 years (range 4–46 years), significantly higher than in the more severely affected XP-A group of patients, who showed progressive neurodegeneration presenting as developmental delay and cognitive impairment, sensorineural hearing loss, microcephaly, neuropathy, and cerebellar signs (Table 1). Remarkably, one of the patients, XP1CB, is aged 79 years without any XP-related neurological problems. He spent the first 30 years of his life in India working mostly outdoors and was only diagnosed clinically at age 46 years. These 12 patients all were homozygous for the mutation c.555+8A>G, which previously was reported by Sidwell et al., 2006Sidwell R.U. Sandison A. Wing J. Fawcett H. Seet J.E. Fisher C. et al.A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma.Br J Dermatol. 2006; 155: 81-88Crossref PubMed Scopus (29) Google Scholar in a 61-year-old Punjabi woman with no neurological problems. All 12 patients included in this study, as well as the case described by Sidwell et al., originate from a 950-km stretch of land around the Northern India/Pakistan/Afghanistan borders (Figure 1i), suggesting a founder effect present in this population.Table 1Summary of clinical features in the XP-A patient cohortXP numberAge (sex)Country of originAge at clinical diagnosisCutaneous featuresSSSDevelopmental/neuropsychometric, and neurological evaluationAge at first mucocutaneous cancer (type)Mutation in XPA geneXP9BI6 (F)Pakistan6Lentigines0Normalc.555+8A>GXP103BR7 (F)Pakistan4Lentigines0Normalc.555+8A>GXP53BR18 (M)Pakistan7Lentigines/photosensitivity1Normalc.555+8A>GXP121BR25 (F)Pakistan25Lentigines1Normalc.555+8A>GXP116BR31 (M)India31Lentigines1Normal31 (BCC)c.555+8A>GXP2PR32 (F)Pakistan32Lentigines1Normalc.555+8A>GXP89BR-S34 (M)Pakistan33Lentigines2Normalc.555+8A>GXP1PR35 (M)Pakistan35Lentigines2Normalc.555+8A>GXP88BR36 (M)Pakistan31Lentigines3Normalc.555+8A>GXP49BR38 (M)Afghanistan24Lentigines/photosensitivity1Normalc.555+8A>GXP89BR43 (F)Pakistan39Photosensitivity3Normalc.555+8A>GXP1CB79 (M)India46Lentigines0Normal46 (MM)c.555+8A>GXP111BR7 (F)Bangladesh5Lentigines3Abnormalc.253C>T p.(Gln85TER)XP57BR14 (F)Bangladesh1Photosensitivity1Abnormalc.640dupA p.(Met214fs)XP80BR14 (F)Somalia8Photosensitivity3Abnormalc.314G>A p.(Cys105Tyr)XP81BR18 (M)Somalia12Photosensitivity1Abnormalc.314G>A p.(Cys105Tyr)XP15BR22 (M)UK0.5Photosensitivity3Abnormalc.266_267dupAA p.(Val90fs)XP114BR24 (M)Pakistan22Photosensitivity3Abnormal22 (SCC)c.682C>T p.(Arg228TER)XP20BR32 (M)Pakistan13Photosensitivity3Abnormal22 (ocular CIN3)c.682C>T p.(Arg228TER)Abbreviations: BCC, basal cell carcinoma; CIN, conjunctival intraepithelial neoplasia; F, female; M, male; MM, malignant melanoma; SCC, squamous cell carcinoma; SSS, sunburn severity score (Sethi et al., 2013Sethi M. Lehmann A.R. Fawcett H. Stefanini M. Jaspers N. Mullard K. et al.Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions.Br J Dermatol. 2013; 169: 1279-1287Crossref PubMed Scopus (54) Google Scholar); XP, xeroderma pigmentosum; XP-A, xeroderma pigmentosum complementation group A. Open table in a new tab Abbreviations: BCC, basal cell carcinoma; CIN, conjunctival intraepithelial neoplasia; F, female; M, male; MM, malignant melanoma; SCC, squamous cell carcinoma; SSS, sunburn severity score (Sethi et al., 2013Sethi M. Lehmann A.R. Fawcett H. Stefanini M. Jaspers N. Mullard K. et al.Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions.Br J Dermatol. 2013; 169: 1279-1287Crossref PubMed Scopus (54) Google Scholar); XP, xeroderma pigmentosum; XP-A, xeroderma pigmentosum complementation group A. The c.555+8A>G mutation at the eighth nucleotide of intron 4 generates a new splice donor site and results in aberrant splicing of intron 4 and nonfunctional, truncated XPA protein. However, there is a small amount of normally spliced mRNA (Sidwell et al., 2006Sidwell R.U. Sandison A. Wing J. Fawcett H. Seet J.E. Fisher C. et al.A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma.Br J Dermatol. 2006; 155: 81-88Crossref PubMed Scopus (29) Google Scholar), which results in production of residual normal XPA protein detectable in immunoblots (Figure 1j). Comparison of the upper XPA band in lanes 9–12 with the calibration in lanes 1–6 suggests that 50-μg extract from the mild XP-A cells has the same amount of (or less) XPA protein as 2.5-μg normal extract (lane 2), indicating the presence of G, we are now able to give cautiously optimistic prognostic information with regard to lack of neurodegeneration and later onset of skin cancer. A diagnosis of mild XP-A should be considered in individuals with facial lentigines, originating from the borders of Northern India, Pakistan, and Afghanistan, as early photoprotection can reduce further development of lentigines and potential skin cancers. Our findings from a relatively small immigrant population in the United Kingdom imply that there may be many such individuals in the area of origin, who are likely to be undiagnosed because of the mildness of symptoms and who may suffer from excessive skin damage later in life. The authors state no conflict of interest. The National Multidisciplinary XP Clinic in the United Kingdom is funded by NHS England Highly Specialised Services. We thank Emma Craythorne (Consultant Dermatological Surgeon), Susie Morley (Consultant Ophthalmologist), Soji Abiona (Consultant Paediatrician), Isabel Garrood (Clinical Neuropsychologist), Paola Giunti (Consultant Neurologist), and Tammy Hedderly (Consultant Paediatric Neurologist) for clinical evaluation of the XP patients. We also thank Tom Callup for help in setting up the sequencing platform. This work was also supported by Medical Research Council (Fellowship Grant No. MR/M001210/1 to MS), the British Skin Foundation (Innovative Project Award Grant No. 5042i to HF), and the UK National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London.