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Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2010.tde-05082010-114429
Document
Author
Full name
Daniela Tathiana Soltys
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2010
Supervisor
Committee
Menck, Carlos Frederico Martins (President)
Barros, Mário Henrique de
Cabral Neto, Januario Bispo
Chammas, Roger
Soares Netto, Luis Eduardo
Title in Portuguese
Análise da natureza genotípica de pacientes Xeroderma pigmentosum brasileiros.
Keywords in Portuguese
Xeroderma pigmentosum
Danos oxidativos
Dermatopatias
Ichthyophiidae
Luz ultravioleta
Reparação de DNA
Variantes alélicas
Abstract in Portuguese
O NER é uma via de reparo de DNA capaz de lidar com uma ampla variedade de lesões. Participam do NER diversas proteínas, entre elas a endonuclease XPG. Pacientes que possuem mutações no gene XPG apresentam a síndrome XP, e em alguns casos XP/CS. Investigamos a natureza genética de dois pacientes XP-G, que são irmãos e apresentam fenótipo moderado. As células destes pacientes demonstraram alta sensibilidade à luz UVC. Quando expostas a um agente oxidativo, apenas células XP-G/CS exibiram sensibilidade. Identificamos duas mutações missense no gene XPG desses pacientes, e comparamos com outras mutações existentes. Observamos que as mutações possuem um impacto negativo na funcionalidade de XPG. A proteína com a mutação p.Ala28Asp exibiu uma atividade residual em testes de complementação. Os resultados indicam que o fenótipo XP-G desses pacientes é causado por duas mutações missense em heterozigose composta, e que células portadoras dessas alterações exibem respostas diferenciadas frente aos estresses genotóxicos causados pela luz UV e pelo agente oxidativo utilizado.
Title in English
Analysis of the genetic nature in brazilian Xeroderma pigmentosum patients.
Keywords in English
Xeroderma pigmentosum
Allelic variants
DNA repair
Ichthyophiidae
Oxidative damage
Skin
Ultravoilet light
Abstract in English
NER is the most flexible of all known DNA repair mechanisms. XPG is an endonuclease that participates in the final steps of NER. Mutations in this gene may result in the human syndrome XP and, in some cases, in the XP/CS. We investigated the genetic nature in two XP-G patients, siblings and mildly affected. The cells from these patients demonstrated the high UV sensitivity typical of this syndrome. When exposed to an oxidative agent, only XP-G/CS cells exhibited sensitivity. We identified two missense mutations in the XPG gene of these patients, and a comparison with other known mutations is presented. These mutations have a negative impact in the function of XPG. The protein harboring the mutation p.Ala28Asp exhibited residual activity in complementation tests. These results indicate that the phenotype of XP-G patients is caused by two missense mutations in a compound heterozygous manner, and that the cells carrying these alterations exhibit different responses against genotoxic stress caused by the UV light and by the oxidative agent used.
 
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Publishing Date
2010-09-17
 
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