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Doctoral Thesis
DOI
10.11606/T.87.2017.tde-22022017-155133
Document
Author
Full name
Ligia Pereira Castro
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2016
Supervisor
Committee
Menck, Carlos Frederico Martins (President)
Galhardo, Rodrigo da Silva
Jorge, Soraia Attie Calil
Okamoto, Oswaldo Keith
Sogayar, Mari Cleide
Title in Portuguese
Caracterização genotípica de pacientes brasileiros com deficiência em processos de reparo de DNA.
Keywords in Portuguese
Cisplatina
Mutações em genes de reparo de DNA
Síndrome de Cockayne
Tricotiodistrofia
Xeroderma Pigmentosum
XP-V
Abstract in Portuguese
Mutações em genes da via de reparo de DNA por excisão de nucleotídeo estão associados a doenças genéticas raras, como Xeroderma pigmentosum, Síndrome de Cockayne e Tricotiodistrofia. Este trabalho teve como objetivo identificar mutações responsáveis por essas Síndromes em pacientes brasileiros. Inicialmente o projeto teve como foco o estudo da comunidade de Araras, no interior de Goiás, onde existe uma das maiores incidências de pacientes XP no mundo. Duas mutações foram identificadas no gene POLH, associadas a dois efeitos fundadores independentes na região. Os dezessete pacientes, entre 10 e 80 anos, caracterizados geneticamente apresentam uma grande heterogeneidade das manifestações clínicas, com fenótipos brandos à extremamente agressivos. Esse estudo se estendeu a mais dezessete pacientes de todo o Brasil, incluindo outros grupos de complementação de XP, CS e TTD. Na segunda parte deste trabalho avaliamos a resposta das linhagens XP-V ao tratamento com cisplatina. Foi possível observar que essas linhagens são mais sensíveis aos danos induzidos pela cisplatina, encontram problemas na fase G1/S de replicação e possuem um aumento da marcação high-level para histona gH2AX.
Title in English
Genotypic characterization of brazillian patients with deficiency in DNA repair processes.
Keywords in English
Cisplatin
Cockayne syndrome
Mutations in DNA repair genes
Trichothiodystrophy
Xeroderma pigmentosum
XP-V
Abstract in English
Mutations at DNA repair genes are associated with rare genetic diseases such as Xeroderma pigmentosum, Cockayne syndrome and Trichothiodystrophy. This study aimed to identify mutations responsible for these syndromes in Brazilian patients. Initially the project focused on the study of Araras community in the state of Goiás, where there is one of the densest known areas of XP patients. Two mutations were identified at POLH gene, associated with two independent founders effects in the region. The seventeen patients between 10 and 80, characterized genetically a wide range of heterogeneity of clinical symptoms with mild to extremely aggressive phenotypes. Brazilian patients from other places were studied, including seventeen other patients with XP, CS and TTD phenotypes. In the second part of this work, we evaluated the response of XP-V cell lines treated with cisplatin. It was observed that Pol eta deficient cells are more sensitive to damage induced by cisplatin, as well as encounter problems in the S phase replication after 24 hours of treatment, and have increased high-level fluorescence for gH2AX.
 
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Release Date
2019-02-23
Publishing Date
2017-02-23
 
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