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Pathogenesis of Rett Syndrome and Study of the Role of Mecp2 Protein in Neuronal Function

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Pathogenesis of Rett Syndrome and Study of the Role of Mecp2 Protein in Neuronal Function Pathogenesis of Rett syndrome and study of the role of MeCP2 protein in neuronal function Mónica Joana Pinto dos Santos Dissertação de doutoramento em Ciências Biomédicas Instituto de Ciências Biomédicas de Abel Salazar Universidade do Porto 2007 Mónica Joana Pinto dos Santos Pathogenesis of Rett syndrome and study of the role of MeCP2 protein in neuronal function Dissertação de Candidatura ao grau de Doutor em Ciências Biomédicas submetida ao Instituto de Ciências Biomédicas de Abel Salazar Universidade do Porto Orientadora – Prof. Doutora Patrícia Espinheira de Sá Maciel Professora Auxiliar ICVS/ECS, Universidade do Minho Co-orientador – Professor Doutor António Jorge dos Santos Pereira de Sequeiros Professor Catedrático Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto Co-orientadora – Professora Doutora Maria Amélia Duarte Ferreira Professora Catedrática Faculdade de Medicina, Universidade do Porto v Aos meus pais “A lua anda devagar, mas atravessa o mundo” (Provérbio Africano) vi vii Preceitos Legais De acordo com o disposto no nº 2 do artigo 8º do Decreto-lei nº 388/70, nesta dissertação foram utilizados os resultados dos trabalhos publicados ou em preparação abaixo indicados. No cumprimento do disposto no referido Decreto-lei, a autora desta dissertação declara que interveio na concepção e execução do trabalho experimental, a interpretação dos resultados e na redacção dos resultados publicados ou em preparação, sob o nome de Santos M: Based on the nº 2 do artigo 8º do Decreto-lei nº 388/70, in this dissertation were used experimental results published or under preparation stated below. The author of this dissertation declares that participated in the planification and execuction of the experimental work, in the data interpretation and in the preparation in the work stated below, under the name Santos M: - Shi J, Shibayama A, Liu Q, Nguyen VQ, Feng J, Santos M , Temudo T, Maciel P, Sommer SS. “Detection of heterozygous deletions and duplications in the MECP2 gene in Rett syndrome by Robust Dosage PCR (RD-PCR)”. Hum Mutat 2005 May;25(5):505. - Santos M , Coelho P and Maciel P “Chromatin remodelling and neuronal function: exciting links ”. Genes Brain & Behavior, 2006 5(suppl. 2): 80-91. - Santos M , Silva-Fernandes A, Oliveira P, Sousa N and Maciel P. “Evidence for abnormal early development in a mouse model of Rett syndrome ”. Genes Brain & Behavior, 2007 Apr 6(3): 277- 86. - Venâncio M, Santos M , Pereira SA, Maciel P, Saraiva MJ. “An explanation for another familial case of Rett syndrome: maternal germline mosaicism.” Eur J Hum Genet. 2007 Aug 15(8):902-4. - Temudo T, Oliveira P, Santos M , Dias K, Vieira JP, Moreira A, Calado E, Carrilho I, Oliveira G, Levy A, Barbot C, Fonseca MJ, Cabral A, Dias A, Lobo Antunes N, Cabral P, Monteiro JP, Borges L, Gomes R, Barbosa C, Santos M, Mira G, Andrada G, Freitas P, Figueiroa S, Sequeiros J and Maciel P. “Stereotypies in Rett Syndrome: analysis of 83 patients with and without detected MECP2 mutations”. Neurology 2007 April 10; 68(15):1183-7. - Coutinho AM, Oliveira G, Katz C, Feng J, Yan J, Yang C, Marques C, Ataíde A, Miguel TS, Temudo T, Santos M , Maciel P, Sommer SS and Vicente AM. “MECP2 coding sequence and 3’UTR variation in 172 unrelated autistic patients”. Am J Med Genet – Part B Neuropsychiatr Genet 2007 Jun 5, 144(4): 475-83. viii - Santos M , Temudo T, Carrilho I, Gaspar I, Barbot C, Medeira A, Cabral H, Oliveira G, Gomes R, Lourenço MT, Venâncio M, Calado E, Moreira A, Maciel P. “Mutations in the MECP2 gene are not a major cause of Rett-like phenotype in male patients”. (Submitted to Genetic Testing). - Santos M , Jin Yan, Temudo T, Jinong F, Sommer S, Maciel P. “Analysis of highly conserved regions of the 3’UTR of the MECP2 gene in patients with clinical diagnosis of Rett syndrome and mental retardation”. (Submitted to Disease Markers). Este trabalho foi co-financiado pela Fundação para a Ciência e Tecnologia (FCT) através de uma bolsa de doutoramento (SFRH/BD/9111/2002) e do projecto (POCTI/41416/2001). This work was funded by Fundação para a Ciência e Tecnologia (FCT) through a PhD fellowship (SFRH/BD/9111/2002) and the project (POCTI/41416/2001). ix Agradecimentos À minha família! Aos meus pais, ao Pedro e à Vera e aos dois mais piquenos, o João e o Quico. Penso que devo começar por eles, pois sem o seu apoio e compreensão jamais teria chegado a esta página. Por terem aceite as longas ausências, os muitos atrasos e a impaciência. São eles a minha terra! À Professora Patrícia Maciel, minha orientadora que foi a minha porta de entrada no mundo da Ciência e um pouco responsável, pelo seu incentivo e entusiasmo contagiante, pela vontade de por cá “ficar”. Ah…e pelo Resumé. Ao Professor Doutor Jorge Sequeiros (ICBAS/UnIGENe), meu co-orientador, por me ter acolhido na sua unidade onde este trabalho se iniciou e pelo seu apoio e interesse demonstrados. À Professora Doutora Amélia Duarte (FMUP), minha co-orientadora, por sempre se ter mostrado disponível para me receber. À Professora Doutora Cecília Leão, directora do ICVS que me recebeu no seu instituto onde a segunda parte deste trabalho decorreu e pela simpatia constante. Ás minhas amigas. Dizem que “longe da vista, longe do coração”, mas a verdadeira amizade sobrevive ao tempo e à distância. Que casa meva és casa vostra! Anabela… gaja! Pela força que me deste nas horas de devaneio em que só me apetecia desistir (não era suposto dizer isto!), por me ouvires durante horas intermináveis e por me dares sempre os melhores conselhos e não os que eu queria ouvir. Pelos muitos porquês… e por todas as respostas, pela companhia na bancada. Por seres só minha amiga. “No comments…”. César….desculpa tê-la alugado tanto tempo. À Andreia de Castro pelos jantares (a altas horas da noite) e longas conversas em nossa casa. Por te levantares sempre primeiro do que eu e me deixares dormir mais um bocadinho, pela compreensão. Pedro Lobo, achas que me esquecia de ti? Sempre que quiseres companhia para uma cerveja e amendoins…e já sabes...”tu não m’ i......” x À Anabela Silva que foi muitas vezes a companhia de muitas horas passadas no biotério. Pelos teus inócuos trocadilhos… bem nem sempre, porque ficará para sempre registrado o famoso “artial marts”. À Fernanda. Tudo bem… até reconheço que no nosso primeiro encontro me enterrei completamente, mas penso que ganhei uma amiga. Foram muitos os bons momentos e foram muitos os maus momentos, mas sem dúvida foram vividos mais intensamente porque os partilhámos. Andreia, Anabela e Fernanda, pelos nossos jantares às sextas, pelos bons e os maus momentos, as longas conversas ou simplesmente o silêncio no “coliseu” lá de casa. À Carmo por ter estado presente sempre que foi preciso. À Ana João pela boa disposição e optimismo constantes. Ao João Sousa pela leitura crítica de alguns capítulos desta tese. À Joana Palha, ao Nuno Sousa e ao Armando Almeida (e Patrícia) que conseguiram formar um verdadeiro grupo nas Neurociências. Obrigada pelas discussões proporcionadas e pela disponibilidade. Ao grupo de Neurociências do ICVS. De certeza que se lerem esta tese vão encontrar um bocadinho do que aprendi com cada um de vocês e dos vossos trabalhos. Ao Professor Pedro Oliveira que com tanta paciência me ajudou a “arranhar a superfície” deste mundo à parte que é a estatística e por ter interrompido constantemente as suas férias para me socorrer. Ao Luís e ao Nuno (Histologia). O que seria de mim sem vocês! A todo o grupo da UnIGENe (2000-2004), onde comecei este trabalho. À FCT pelo apoio financeiro para a execução deste trabalho, nomeadamente pela bolsa de doutoramento concedida. Às crianças com síndrome de Rett e aos seus pais. É pequeno o meu contributo, mas é para vós. xi Resumo A síndrome de Rett (RTT) é uma doença do neurodesenvolvimento que afecta quase exclusivamente meninas. Depois de um período de aparente desenvolvimento normal entre 6-18 meses segue-se uma paragem no desenvolvimento seguida de uma deterioração das capacidades motora, autonómica, social e intelectual. As pacientes com RTT apresentam doença do movimento (ataxia e apraxia), comportamento autista, estereotipias manuais e atraso mental. Além desta apresentação dita clássica da síndrome, as formas variantes incluem fenótipos mais suaves e outros mais graves, assim como uma forma variante que afecta meninos, geralmente mais grave devido à hemizigotia do cromossoma X. Mutações no gene que codifica uma proteína de ligação aos metil-CpG ( MECP2 ) são a causa primária de RTT (>90% nos casos clássicos e 30% nos atípicos). No entanto, mutações no MECP2 também foram encontradas, com uma frequência mais baixa, em indivíduos com outras doenças do neurodesenvolvimento parcialmente sobrepostas a RTT, como por exemplo autismo, atraso mental não sindrómico e síndrome de Angelman. As mutações no MECP2 ocorrem por todo o gene e são de vários tipos. Apesar disto, uma proporção significativa de casos com RTT permanece sem uma causa genética identificada, o que sugere o envolvimento de regiões não codificantes do MECP2 ou de outros genes nesta patologia. A principal função da proteína MeCP2 é a de repressora da transcrição. A MeCP2 liga-se ao DNA metilado e actua recrutando as proteínas Sin3A e histonas desacetilases formando-se um complexo que vai desacetilar as histonas e assim reprimir a transcrição. Mutações na MeCP2 vão assim causar uma desregulação da transcrição de genes alvo. No entanto, outras funções da MeCP2 podem também ser afectadas, uma vez que certas mutações na MeCP2 que não afectam a sua capacidade de repressão ocorrem em locais de ligação da MeCP2 a outras proteínas. O nosso objectivo neste estudo é “mapear” a ocorrência de certas mutações no gene MECP2 fazendo-as corresponder a determinados fenótipos nos humanos e no ratinho para assim melhor compreender o mecanismo patogénico subjacente à variabilidade fenotípica de RTT, em particular à disfunção motora.
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