Abstract
Xeroderma pigmentosum (XP) is a rare disorder characterized by a high skin sun-sensitivity predisposing to skin cancers at an early age. Among Tunisian XP patients with an intermediate skin phenotype, 92% presented neurological abnormalities related to XPA gene deficiency. Clinical variability of the XP-A phenotype is associated with a mutational heterogeneity. In the present study, two Tunisian families with severe dermatological and neurological XP phenotypes were investigated in order to determine clinical characteristics and genetic basis. Two Tunisian families with four XP affected children were examined in the Dermatology Department. Clinical features showed severe presentation of the disease. Coding regions of the XPA gene were analysed by direct sequencing. Results showed the presence of a novel mutation, p.E111X, in three patients belonging to the same family and presenting a very severe phenotype i.e. development of skin lesions and neurological signs before 1 year age. For the other patient, we identified a nonsense mutation, p.R207X, already identified in a Palestinian XP-A patient. Identification of novel causing mutations in Tunisian XP-A patients shows the genetic and mutational heterogeneity of the disease in Tunisia. Despite a relatively homogenous mutational spectrum, mutational heterogeneity for rare cases is observed because of the high rate of consanguinity.
Similar content being viewed by others
Notes
References
Ben Rekaya M, Messaoud O, Talmoudi F, Nouira S, Ouragini H, Amouri A, Boussen H, Boubaker S, Mokni M, Mokthar I, Abdelhak S, Zghal M (2009) High frequency of the V548A fs X572 XPC mutation in Tunisia: implication for molecular diagnosis. J Hum Genet 54:426–429
Hirai Y, Kodama Y, Moriwaki S, Noda A, Cullings HM, Macphee DG, Kodama K, Mabuchi K, Kraemer KH, Land CE, Nakamura N (2006) Heterozygous individuals bearing a founder mutation in the XPA DNA repair gene comprise nearly 1% of the Japanese population. Mutat Res 601:171–178
Inui H, Oh KS, Nadem C, Ueda T, Khan SG, Metin A, Gozukara E, Emmert S, Slor H, Busch DB, Baker CC, DiGiovanna JJ, Tamura D, Seitz CS, Gratchev A, Wu WH, Chung KY, Chung HJ, Azizi E, Woodgate R, Schneider TD, Kraemer KH (2008) Xeroderma pigmentosum-variant patients from America, Europe, and Asia. J Invest Dermatol 128:2055–2068
Koberle B, Roginskaya V, Wood RD (2006) XPA protein as a limiting factor for nucleotide excision repair and UV sensitivity in human cells. DNA Repair (Amst) 5:641–648
Kondoh M, Ueda M, Ichihashi M (1994) Correlation of the clinical manifestations and gene mutations of Japanese xeroderma pigmentosum group A patients. Br J Dermatol 133:579–585
Kraemer KH, Lee MM, Scotto J (1987) Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 123:241–250
Lehmann AR (2003) DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Biochimie 11:1101–1111
Messaoud O, Ben Rekaya M, Cherif W, Talmoudi F, Boussen H, Mokhtar I, Boubaker S, Amouri A, Abdelhak S, Zghal M (2010) Genetic homogeneity of mutational spectrum of group-A xeroderma pigmentosum in Tunisian patients. Int J Dermatol 49:544–548
Messaoud O, Ben Rekaya M, Kefi R, Chebel S, Boughammoura-Bouatay A, Bel Hadj Ali H, Gouider-Khouja N, Zili J, Frih-Ayed M, Mokhtar I, Abdelhak S, Zghal M (2010) Identification of a primarily neurological phenotypic expression of xeroderma pigmentosum complementation group A in a Tunisian family. Br J Dermatol 162:883–886
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
Nishigori C, Moriwaki SI, Takebe H, Tanaka T, Imamura S (1994) Gene alterations and clinical characteristics of xeroderma pigmentosum group A patients in Japan. Arch Dermatol 130:191–197
Nishigori C, Zghal M, Yagi T, Imamura S, Komoun MR, Takebe H (1993) High prevalence of the point mutation in exon 6 of the xeroderma pigmentosum group A-complementing (XPAC) gene in xeroderma pigmentosum group A patients in Tunisia. Am J Hum Genet 53:1001–1006
Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH (2000) Cockayne syndrome and xeroderma pigmentosum. Neurology 55:1442–1449
Rivera-Begeman A, McDaniel LD, Schultz RA, Friedberg EC (2007) A novel XPC pathogenic variant detected in archival material from a patient diagnosed with xeroderma pigmentosum: a case report and review of the genetic variants reported in XPC. DNA Repair (Amst) 6:100–114
Satokata I, Tanaka K, Miura N, Narita M, Mimaki T, Satoh Y, Kondo S, Okada Y (1992) Three nonsense mutations responsible for group A xeroderma pigmentosum. Mutat Res 273:193–202
Sidwell RU, Sandison A, Wing J, Fawcett HD, Seet JE, Fisher C, Nardo T, Stefanini M, Lehmann AR, Cream JJ (2006) 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 155:81–88
Soufir N, Ged C, Bourillon A, Austerlitz F, Chemin C, Stary A, Armier J, Pham D, Khadir K, Roume J, Hadj-Rabia S, Bouadjar B, Taieb A, de Verneuil H, Benchiki H, Grandchamp B, Sarasin A (2010) A prevalent mutation with founder effect in xeroderma pigmentosum group C from North Africa. J Invest Dermatol 130:1537–1542
States JC, McDuffie ER, Myrand SP, McDowell M, Cleaver JE (1998) 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 12:103–113
Wood RD (1996) DNA repair in eukaryotes. Annu Rev Biochem 65:135–167
Zhang W, Bouffard GG, Wallace SS, Bond JP, NISC Comparative Sequencing Program (2007) Estimation of DNA sequence context-dependent mutation rates using primate genomic sequences. J Mol Evol 65:207–214
Acknowledgments
We would like to thank the patients and their families as well as the patients’ support group “Helping Xeroderma Pigmentosum children”Footnote 1 for their collaboration. This work was supported by the Tunisian Ministry of Higher Education and Scientific Research (Research Unit on “Molecular Investigation of Genetic Orphan Diseases” UR 04/SP03) and the Tunisian Ministry of Public Health.
Author information
Authors and Affiliations
Corresponding author
Additional information
O. Messaoud and M. Ben Rekaya contributed equally to this article.
Rights and permissions
About this article
Cite this article
Messaoud, O., Ben Rekaya, M., Ouragini, H. et al. Severe phenotypes in two Tunisian families with novel XPA mutations: evidence for a correlation between mutation location and disease severity. Arch Dermatol Res 304, 171–176 (2012). https://doi.org/10.1007/s00403-011-1190-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00403-011-1190-4