title: Severe phenotypes in two Tunisian families with novel XPA mutations: evidence for a correlation between mutation location and disease severity.
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.
authors.affiliation: "Molecular Investigation of Genetic Orphan Diseases" Research Unit, Pasteur Institute of Tunis, Tunisia.
authors.forename: O
authors.initials: O
authors.lastname: Messaoud
authors.forename: M Ben
authors.initials: MB
authors.lastname: Rekaya
authors.forename: H
authors.initials: H
authors.lastname: Ouragini
authors.forename: S
authors.initials: S
authors.lastname: Benfadhel
authors.forename: H
authors.initials: H
authors.lastname: Azaiez
authors.forename: R
authors.initials: R
authors.lastname: Kefi
authors.forename: N
authors.initials: N
authors.lastname: Gouider-Khouja
authors.forename: I
authors.initials: I
authors.lastname: Mokhtar
authors.forename: A
authors.initials: A
authors.lastname: Amouri
authors.forename: M S
authors.initials: MS
authors.lastname: Boubaker
authors.forename: M
authors.initials: M
authors.lastname: Zghal
authors.forename: S
authors.initials: S
authors.lastname: Abdelhak
mesh_terms: D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D014416:Tunisia; D014983:Xeroderma Pigmentosum / Q000235:genetics* / Q000503:physiopathology; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein