V Munford1, L P Castro1, R Souto2, L K Lerner1, J B Vilar1, C Quayle1, H Asif1, A P Schuch1,3, T A de Souza1, S Ienne1, F I A Alves1, L M S Moura1, P A F Galante4, A A Camargo4, R Liboredo5, S D J Pena5, A Sarasin6, S C Chaibub7, C F M Menck1. 1. Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil. 2. Secretariat of Health, Goiania, GO, Brazil. 3. Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Santa Maria, RS, Brazil. 4. Molecular Oncology Center, Hospital Sírio-Libanês, São Paulo, SP, Brazil. 5. Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. 6. UMR 8200 CNRS, Institut Gustave Roussy and University Paris-Saclay, Villejuif, France. 7. General Hospital of Goiania, Goiania, GO, Brazil.
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.
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.
Authors: Têmis Maria Félix; Bibiana Mello de Oliveira; Milena Artifon; Isabelle Carvalho; Filipe Andrade Bernardi; Ida V D Schwartz; Jonas A Saute; Victor E F Ferraz; Angelina X Acosta; Ney Boa Sorte; Domingos Alves Journal: Orphanet J Rare Dis Date: 2022-02-24 Impact factor: 4.123
Authors: Andrew M Armenta; Paul R Massey; Sikandar G Khan; Deborah Tamura; Moise L Levy; John J DiGiovanna; Kenneth H Kraemer; Matthew C Fox Journal: JAAD Case Rep Date: 2018-11-14
Authors: Maria Claudia Schelini; Luis Fernando O B Chaves; Marcia C Toledo; Francisco W Rodrigues; Tauan de Oliveira; David L C Isaac; Marcos Avila Journal: J Ophthalmol Date: 2019-10-31 Impact factor: 1.909