ABSTRACT
BACKGROUND: Xeroderma pigmentosum (XP) is a rare human syndrome associated with hypersensitivity to sunlight and a high frequency of skin tumours at an early age. We identified a community in the state of Goias (central Brazil), a sunny and tropical region, with a high incidence of XP (17 patients among approximately 1000 inhabitants). OBJECTIVES: To identify gene mutations in the affected community and map the distribution of the affected alleles, correlating the mutations with clinical phenotypes. METHODS: Functional analyses of DNA repair capacity and cell-cycle responses after ultraviolet exposure were investigated in cells from local patients with XP, allowing the identification of the mutated gene, which was then sequenced to locate the mutations. A specific assay was designed for mapping the distribution of these mutations in the community. RESULTS: Skin primary fibroblasts showed normal DNA damage removal but abnormal DNA synthesis after ultraviolet irradiation and deficient expression of the Polη protein, which is encoded by POLH. We detected two different POLH mutations: one at the splice donor site of intron 6 (c.764 +1 G>A), and the other in exon 8 (c.907 C>T, p.Arg303X). The mutation at intron 6 is novel, whereas the mutation at exon 8 has been previously described in Europe. Thus, these mutations were likely brought to the community long ago, suggesting two founder effects for this rare disease. CONCLUSIONS: This work describes a genetic cluster involving POLH, and, particularly unexpected, with two independent founder mutations, including one that likely originated in Europe.
Subject(s)
Founder Effect , Mutation/genetics , Skin Neoplasms/genetics , Xeroderma Pigmentosum/genetics , Adult , Aged , Aged, 80 and over , Brazil/ethnology , Europe/ethnology , Female , Heterozygote , Homozygote , Humans , Male , Middle Aged , Pedigree , Tumor Cells, Cultured , Xeroderma Pigmentosum/ethnologyABSTRACT
The genomic integrity of all living organisms is constantly jeopardized by physical [e.g. ultraviolet (UV) light, ionizing radiation] and chemical (e.g. environmental pollutants, endogenously produced reactive metabolites) agents that damage the DNA. To overcome the deleterious effects of DNA lesions, nature evolved a number of complex multi-protein repair processes with broad, partially overlapping substrate specificity. In marked contrast, cells may use very simple repair systems, referred to as direct DNA damage reversal, that rely on a single protein, remove lesions in a basically error-free manner, show high substrate specificity, and do not involve incision of the sugar-phosphate backbone or base excision. This concise review deals with two types of direct DNA damage reversal: (i) the repair of alkylating damage by alkyltransferases and dioxygenases, and (ii) the repair of UV-induced damage by spore photoproduct lyases and photolyases. (Part of a Multi-author Review).
Subject(s)
DNA Damage , DNA Repair , Models, Molecular , Alkyl and Aryl Transferases/chemistry , Alkyl and Aryl Transferases/genetics , Alkyl and Aryl Transferases/metabolism , Alkylating Agents/toxicity , Animals , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Deoxyribodipyrimidine Photo-Lyase/chemistry , Deoxyribodipyrimidine Photo-Lyase/genetics , Deoxyribodipyrimidine Photo-Lyase/metabolism , Dioxygenases/chemistry , Dioxygenases/genetics , Dioxygenases/metabolism , Phylogeny , Ultraviolet Rays/adverse effectsABSTRACT
The applicability of SBA-15 mesostructure as an adjuvant and evaluation of its efficiency to induce antibody response, was discussed. It was observed that better encapsulation of biomolecules of variable shape and size can be achieved using a antigen to SBA-15 weight ratio of 1: 2.5. Efficient antibody generation could be achieved because SBA-15 was able to attract antigens effectively due to its high surface area and proper mesopore size. The results show that SBA-15 and related silica mesostructures are promising nanosystems for vaccine delivery.
