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Nathalialisboarosaalmeidago NATHÁLIA LISBOA ROSA ALMEIDA GOMES Novas perspectivas no diagnóstico etiológico dos distúrbios do desenvolvimento sexual 46,XY Tese apresentada à Faculdade de Medicina da Universidade de São Paulo para obtenção do título de Doutor em Ciências Programa de Ciências Médicas Área de concentração: Distúrbios Genéticos do Desenvolvimento e Metabolismo Orientadora: Profa. Dra. Berenice Bilharinho de Mendonça (Versão corrigida. Resolução CoPGr 6018/11, de 1 de novembro de 2011. A versão original está disponível na Biblioteca da FMUSP) São Paulo 2019 Dados Internacionais de Catalogação na Publicação (CIP) Preparada pela Biblioteca da Faculdade de Medicina da Universidade de São Paulo ©reprodução autorizada pelo autor Gomes, Nathália Lisboa Rosa Almeida Novas perspectivas no diagnóstico etiológico dos distúrbios do desenvolvimento sexual 46,XY / Nathália Lisboa Rosa Almeida Gomes. -- São Paulo, 2019. Tese(doutorado)--Faculdade de Medicina da Universidade de São Paulo. Programa de Ciências Médicas. Área de Concentração: Distúrbios Genéticos de Desenvolvimento e Metabolismo. Orientadora: Berenice Bilharinho de Mendonça. Descritores: 1.Transtornos do desenvolvimento sexual 2.Disgenesia gonadal 46 XY 3.Sequenciamento completo do exoma 4.Gene DHX37 5.Sequenciamento de nucleotídeos em larga escala 6.Gene NR5A1 USP/FM/DBD-347/19 Responsável: Erinalva da Conceição Batista, CRB-8 6755 Este trabalho foi desenvolvido na Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42 da Disciplina de Endocrinologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo com apoio financeiro da Fundação de Amparo à Pesquisa do estado de São Paulo (FAPESP) por meio do processo 2015/21948-8. Dedicatória A Deus, por trilhar meu caminho e me dar coragem para seguir em frente. Ao meu marido, Bernardo, meu grande incentivador, pelo amor incondicional. Por partilhar dos meus sonhos e por me fazer acreditar de que eu era capaz, desde o princípio. Agradecimentos Após estes 4 anos, escrever algumas páginas de agradecimentos me parece pouco. Esta linda caminhada só foi possível pelas pessoas que me auxiliaram a trilhá-la. À minha querida orientadora Dra. Berenice, agradeço pelo acolhimento, com todo o carinho, e pelo incentivo constante, com ideias brilhantes. Por seu exemplo de liderança e pela preocupação com o próximo. A sua simplicidade e amabilidade trazem para perto de si várias pessoas especiais, que tornam o LIM42 um local prazeroso e feliz de trabalhar, deixando tudo mais leve. Por me introduzir na genética e nesta parte tão especial da endocrinologia que é o desenvolvimento. Tudo o que adquiri neste período me trouxe um legado profissional e pessoal inestimável, que irá perdurar para a vida inteira. Muito obrigada! Aos meus pais, João Carlos e Marlene, por serem a base de tudo; por me ensinarem a ter sonhos e me estimularem a correr atrás deles. Mesmo não sendo médicos, vocês me ensinaram a focar no que realmente importa: o paciente. À minha irmã, Victória, por dividir experiências comigo desde sempre, por fazer minha vida sempre ser mais leve. Aos amigos da sala do DDS! Rafa, Jota, Dani: conseguimos compor um quarteto equilibrado, cada qual com sua qualidade, que agregou uma mistura boa de parceria, troca de experiências e muitas risadas. Compartilhamos desde angústias a momentos inenarráveis em alguns congressos pelo mundo. O que é bom deve perdurar por toda a vida! As conquistas foram possíveis por estarmos juntos! À Flavinha, primeira a me acolher, obrigada pelo carinho! Lia e Maria Tereza, as últimas agregadas, que, em pouco tempo de convivência, estiveram comigo em momentos muito difíceis, mas também em outros de muita comemoração. À Marlene Inácio, nossa psicóloga e amiga, pela leveza trazida aos atendimentos e às nossas manhãs de quarta-feira. Muito obrigada por serem pessoas tão especiais! À Janaína, amiga-irmã desde a faculdade, com quem tive a sorte de conviver (intensamente) e dividir meu cotidiano nos últimos anos. Nos apoiamos nesta jornada: você, na medicina fetal e eu, na endocrinologia, com idas e vindas semanais de Belo Horizonte. Sua autenticidade, coragem e vontade de ser feliz me inspiraram e inspiram a cada dia. Às amigas de infância e de vida, especialmente à Maysa, Taty e Bruna. Sabemos que sozinho ninguém vai longe e vocês me fortaleceram nesta caminhada. Olhando para trás, sou orgulhosa de nossa determinação, apoio mútuo e progresso, cada uma em sua profissão. Agradeço ao amigo Bernardo que, mesmo estando tão distante, se fez tão perto e me auxiliou em parte deste trabalho. Agradeço às famílias Gomes, Rosa e Ferreira pela torcida constante! Por entenderem minhas ausências e sempre me receberem com calorosos abraços de conforto. Às queridas Dra. Sorahia e Dra. Elaine, por todos os ensinamentos, pela paciência e pelas oportunidades. Vocês foram alicerces nesta jornada, auxiliando a organizar a nossa casuística, os dados pregressos, contando com memórias invejáveis. À Dra. Ana Claudia Latrônico, pelo estímulo dado desde o nosso primeiro encontro, com todo o seu brilhantismo e amor pela pesquisa. Sua determinação e postura me inspiraram. Aos amigos da pós-graduação: Isa, Helaine, Letícia, Ju, Tathy e meninas da reunião do grupo do GH, pelos cafés e almoços, experiências compartilhadas de profissão e de vida, pelos aprendizados e momentos divertidos em congressos. Com todo o apoio e a torcida mútua, a caminhada ficou mais fácil. À Thatiana Silva, em especial, pela perseverança com todo o trabalho do gene DHX37. Ao Dr. Alexander Jorge, por toda a dedicação e empolgação contagiantes pelas pesquisas da genética endocrinológica. Agradeço por partilhar comigo os ensinamentos nas análises, desde os primeiros passos. Ao Dr. Ivo, pelo carinho, pelo bom senso e pelas opiniões, que engrandeceram os trabalhos publicados. Minha eterna admiração. Ao Dr. Antônio Lerário, nosso bioinformata, indispensável para a execução deste trabalho. Mesmo à distancia, se fez presente, solucionando minhas dúvidas. À Mirian, Mônica, Luciana Montenegro e Mariana Funari, pela amizade, pela dedicação e pelo auxílio à análise dos dados. À Carol, meu braço direito na bancada. Vocês foram parte fundamental no sucesso desta tese. À Dra. Tania Bachega, Dr. Madson Almeida, Dra. Luciani Carvalho, Dra. Larissa Gomes, Dr. Vinicius Brito, Dra. Regina Matsunaga, Dra. Letícia Gontijo, Dra. Maria Cândida Fragoso e Dra. Guiomar Madureira, pela receptividade em suas salas de atendimento, pelas enriquecedoras discussões e auxílio nos casos que atendo em Belo Horizonte. Devo meu conhecimento adquirido na área de suprarrenal e gônadas a vocês! Aos mestres da endocrinologia e atuais colegas da Santa Casa de Belo Horizonte, por fazerem parte da base de minha formação endocrinológica e, especialmente, por me acolherem como membro do corpo clínico nos ambulatórios de adrenal e crescimento, propiciando, mais uma vez, meu crescimento profissional. Sou eternamente grata pelo carinho e confiança. A todos os funcionários do LIM42, especialmente às queridas secretárias Nildinha e Rosângele, Cidinha, Luciana Brito, Fran, Cris, Valéria, Neide, Gislene, pela competência, por sempre trabalharem com alegria, em um clima amigável regado a lanches e cafés, sem deixar passar em branco as comemorações. Um abraço a todos pelo carinho. Aos funcionários da endocrinologia, Rubens e Roberta, pela disponibilidade e pelo auxílio. A todas as colaborações nacionais e internacionais, especialmente à Dra. Leila Pedrosa, por compartilharem seus pacientes para estudo genético e por nos fornecerem o aparato necessário para ampliarmos os conhecimentos adquiridos neste trabalho. E, por fim, aos pacientes e familiares, por serem o motivo principal deste trabalho, pela confiança! Sem vocês, nada disso seria possível. Normalização Esta tese está de acordo com as seguintes normas, em vigor no momento desta publicação: Referências: adaptado de International Committee of Medical Journals Editors (Vancouver). Universidade de São Paulo, Faculdade de Medicina. Divisão de Biblioteca e Documentação. Guia de apresentação de dissertações, teses e monografias. Elaborado por Anneliese Carneiro da Cunha, Maria Julia de A. L. Freddi, Maria F. Crestana, Marinalva de Souza Aragão, Suely Campos Cardoso, Valéria Vilhena, 3ª ed. São Paulo: Divisão de Biblioteca e documentação; 2011. Abreviaturas dos títulos dos periódicos de acordo com List of Journals Indexed in Index Medicus. Sumário Lista de abreviaturas Lista de símbolos de genes Lista de figuras Lista de tabelas Resumo Abstract 1 Introdução .................................................................................................. 1 1.1 Mecanismos envolvidos no desenvolvimento sexual ........................ 2 1.2 Distúrbios/diferenças do Desenvolvimento Sexual ............................ 5 1.3 Determinação da etiologia dos DDS 46,XY ....................................... 6 1.4 Diagnóstico molecular dos DDS 46,XY pelo sequenciamento pelo método de Sanger ..................................................................... 9 1.5 Sequenciamento paralelo em larga escala (SPLE) para o diagnóstico molecular dos DDS 46,XY ............................................ 10 1.6 DEAH-box helicase 37 (DHX37): novo gene candidato à etiologia dos DDS 46,XY disgenéticos ............................................ 12 2 Justificativa ............................................................................................. 14 3 Objetivos .................................................................................................
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