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Cellular and molecular characterization of Xeroderma pigmentosum brazilian patients

Grant number: 13/17513-0
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): November 01, 2013
Effective date (End): October 31, 2016
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal researcher:Carlos Frederico Martins Menck
Grantee:Ligia Pereira Castro
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


This project aims to determine the genetic mutations and their effects on cells from patients clinically diagnosed with Xeroderma Pigmentosum Variant (XP-V) in Brazil. During the masters degree this study aimed to characterize genotypically XP-V patients in the community located at Faina, Goiás. Two mutations (exchange basis) were found in the XPV gene: one of them is located in a splicing donor site, at an exon-intron boundaries, and the other one caracterize a stop codon signaling. Moreover, during the masters was developed a molecular test for genotyping the two mutations found in the community, and currently able to obtain samples from that population, which will, together with the genealogy developed previously, to better understand how these mutations were transmitted through the generations. The mRNA analysis by real-time PCR, with primers at the exon 6 and 7 junction, showed a 30% reduction in the mRNA relative expression from the heterozygous sample for the two mutations and differently, from the homozygous sample for the mutation at the splicing site, where this expression is zero. In fibroblasts from another Brazilian patient, was identified a homozygous mutation at a splicing site before the last exon of the XPV gene, which might be resulted in a relative mRNA expression of this gene six times higher compared to control. Furthermore, we found that these cells that contain different mutations in the same gene, they differ in the cellular response to treatment with cisplatin. Other chemotherapy should be addressed to study the sensitivity of these strains facing the different lesions induced by different treatments as doxorubicin (Doxo) and nimustine (ACNU). Our goal in this project is to analyze how the processing is occurring and mRNA stability XPV gene in these cells. The correlation responses of these cells to DNA damage (induced by ultraviolet or cisplatin) and identifying the expression levels and mRNA transcripts and eventually the proteins produced may help to understand the different clinical phenotype of the patients. Moreover, during the masters was developed a molecular test to identify the two mutations found at the community. Thus, the current project has the interest, along with the family tree developed during the masters, to better understand how these mutations were transmitted over generations. (AU)

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Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
CASTRO, Ligia Pereira. Genotypic characterization of brazillian patients with deficiency in DNA repair processes.. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.

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