RESSALVA Atendendo solicitação do(a) autor(a), o texto completo desta tese será disponibilizado somente a partir de 09/08/2025. UNIVERSIDADE ESTADUAL PAULISTA “JÚLIO DE MESQUITA FILHO” FACULDADE DE MEDICINA Igor de Carvalho Deprá Síndrome de Resistência ao Hormônio Tireoidiano: Mecanismos e Manifestações Clínicas Tese apresentada à Faculdade de Medicina, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Câmpus de Botucatu, para obtenção do título de Doutor em Fisiopatologia em Clínica Médica. Orientadora: Profa. Dra. Célia Regina Nogueira Coorientadora: Dra. Maria Cristina Crês Botucatu 2024 Igor de Carvalho Deprá Síndrome de Resistência ao Hormônio Tireoidiano: Mecanismos e Manifestações Clínicas Tese apresentada à Faculdade de Medicina, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Câmpus de Botucatu, para obtenção do título de Doutor em Fisiopatologia em Clínica Médica. Orientadora: Profa. Dra. Célia Regina Nogueira Coorientadora: Dra. Maria Cristina Crês Botucatu 2024 FICHA CATALOGRÁFICA ELABORADA PELA SEÇÃO TÉC. AQUIS. TRATAMENTO DA INFORM. DIVISÃO TÉCNICA DE BIBLIOTECA E DOCUMENTAÇÃO - CÂMPUS DE BOTUCATU - UNESP BIBLIOTECÁRIA RESPONSÁVEL: ROSANGELA APARECIDA LOBO-CRB 8/7500 Deprá, Igor de Carvalho. Síndrome de resistência ao hormônio tireoidiano : mecanismos, manifestações clínicas e implicações terapêuticas / Igor de Carvalho Deprá. - Botucatu, 2024 Tese (doutorado) - Universidade Estadual Paulista (UNESP), Faculdade de Medicina, Botucatu Orientador: Célia Regina Nogueira Coorientador: Maria Cristina Crês Capes: 40101061 1. Glândula tireóide. 2. Hormônios tireóideos. 3. Receptores beta dos hormônios tireóideos. 4. Genética. 5. Genes. Palavras-chave: Síndrome de resistência ao hormônio tireoidiano; THRB; Tireoide. DEDICATÓRIA À minha filha Amélie AGRADECIMENTOS À minha orientadora, a quem devo tantas oportunidades; À Dra. Maria Cristina Crês, que gentilmente colaborou neste processo; A Francisco, Mariella e Simone, a quem um dia retribuirei; À Unidade de Pesquisa Experimental e ao Instituto de Biotecnologia, pelo apoio generoso à realização deste projeto; Aos colegas de laboratório, por compartilhar os altos e baixos desta experiência; Aos meus familiares, pela paciência; À Dra. Gláucia M. F. S. Mazeto, pelo incentivo; A todos os que me estimularam a seguir adiante. “Não se devia permitir nos relógios de parede esses ponteiros que marcam os segundos: eles nos envelhecem muito mais que o ponteiro das horas.” Mário Quintana Resumo A síndrome de resistência ao hormônio tireoidiano beta (RHTβ) é causada por mutações no gene codificante da isoforma beta do receptor de hormônio tireoidiano (THRB). Caracterizada bioquimicamente pela elevação sérica de tiroxina (T4) sem supressão do hormônio tireoestimulante (TSH), possui manifestação clínica variada, podendo afetar diferentes órgãos, e sua peculiaridade está na manifestação simultânea de sinais de hipo e hipertireoidismo. Recentemente, foi descrita uma mutação previamente desconhecida, substituindo a leucina do códon 341 por valina (L341V), que causa RHTβ, porém com pouca informação sobre a manifestação clínica. Neste estudo, foi acompanhada a evolução clínica da síndrome em uma família não relacionada, também portadora da mutação L341V, ao longo de 13 anos, encontrando características ausentes na literatura. Abstract Thyroid hormone resistance syndrome beta (THRβ) is caused by mutations in the gene coding the beta isoform of thyroid hormone receptor (THRB). Biochemically, it is characterized by elevation of serum thyroxine (T4) with unsuppressed thyrostimulating hormone (TSH), and has variable clinical manifestation, potentially affecting various organ systems. Its peculiarity resides in the simultaneous occurence of hipo- and hiperthyroidism hallmarks. It has been recently described a novel mutation, substituting leukine for valine in codon 341 of THRB, causing THRβ, though little information was reported on its clinical manifestation. This study reports the 13-year follow up of an unrelated family, also harboring the L341V mutation, finding characteristics previously absent in the literature. Sumário 1. Introdução............................................................................................................8 1.1. Ação fisiológica dos hormônios tireoidianos (HT).........................................8 1.2. Receptores de HT (TR) e seus mecanismos de ação................................12 1.3. Síndrome de resistência a hormônio tireoidiano tipo β (RHTβ)..................15 1.4. Outras síndromes de resistência ao hormônio tireoidiano.........................20 1.5. Justificativa.................................................................................................25 1.6. Objetivo......................................................................................................25 2. Referências........................................................................................................26 3. Artigo.................................................................................................................40 Resumo.............................................................................................................41 Introdução..........................................................................................................41 Pacientes e métodos.........................................................................................43 Resultados.........................................................................................................44 Discussão..........................................................................................................47 Conclusão..........................................................................................................48 Referências.......................................................................................................49 4. Anexo.................................................................................................................52 4.1. Métodos suplementares – Extração de DNA de raspagem bucal..............52 4.2. Métodos suplementares – Reação em cadeia da polimerase (PCR).........52 4.3. Métodos suplementares – Purificação das PCRs......................................53 4.4. Métodos suplementares – Sequenciamento Sanger..................................53 4.5. Resultados suplementares.........................................................................55 1. Introdução 1.1. Ação fisiológica dos hormônios tireoidianos (HT) A capacidade de produzir ou metabolizar hormônios tireoidianos (HT) é encontrada amplamente no reino animal. Seus efeitos no desenvolvimento embrionário e larval são observados em diversos grupos de invertebrados, incluindo moluscos e equinodermos [1]. Em cordados, determinam o início da metamorfose de peixes [2] e anfíbios [3], e são indispensáveis para o desenvolvimento do sistema nervoso central [4,5] o que é demonstrado pelos efeitos deletérios do hipotireoidismo congênito no desenvolvimento cerebral em humanos [6]. No indivíduo adulto, alguns de seus efeitos mais notáveis incluem o controle da taxa metabólica basal e da produção de calor [7], além de funções fisiológicas concomitantes, como regulação do apetite [8], cujo efeito último é suprir os tecidos estimulados com os nutrientes necessários para sustentar o metabolismo. Há, ainda, efeitos tratados como pleiotrópicos por não terem relação óbvia com as alterações metabólicas, como a aceleração do turnover ósseo [9]. Em vertebrados, os HT são produzidos pela glândula tireoide, cujo parênquima consiste de estruturas globulares microscópicas denominadas folículos, preenchidas por uma substância coloidal e delimitadas por um epitélio simples de células foliculares. A partir dessa substância coloidal, as células foliculares sintetizam e secretam duas formas de HT, L-tiroxina (T4), sendo esta a forma majoritária, e 3,5,3´-triiodo-L-tironina (T3). Na circulação, cerca de 0,03% do T4 e 0,3% do T3 encontram-se livres, estando a maior fração ligada à globulina ligadora de tiroxina (TBG) e, em menor proporção, à transtirretina (TTR) e à albumina sérica, o que contribui para a estabilização dos níveis séricos de HT, cuja regulação será detalhada a seguir [10]. 1.1.1. Regulação das concentrações de HT Sistemicamente, as concentrações de HT circulantes são mantidas dentro de um intervalo estreito pelo sistema de feedback negativo conhecido como eixo hipotálamo-hipófise-tireoide. A produção e secreção de HT pela glândula tireoide depende de estímulo por hormônio tireoestimulante, ou tireotropina (TSH), produzido 8 2. Referências 1. Taylor, E.; Heyland, A. Evolution of thyroid hormone signaling in animals: Non- genomic and genomic modes of action. 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