Pathogenic SOX2 variants typically cause severe ocular defects within a SOX2-disorder spectrum that includes hypogonadotropic hypogonadism (HH). We examined exome sequencing data from a large, well-phenotyped cohort of patients (n=1453) with Idiopathic Hypogonadotropic Hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified eight IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists.We found that Sox2 is highly expressed in the hypothalamus of adult mice and colocalizes with KISS1 expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increases the levels of human kisspeptin luciferase transcription (hKISS-luc), while SOX2 overexpression represses hKiss-luc transcription. Further, four of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH attesting to hypothalamic defects in the SOX2disorder spectrum. Our study describes novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.
Gostaria de agradecer primeiramente à minha orientadora Mariz Vainzof, que tem um papel fundamental no desenvolvimento deste trabalho e crescimento acadêmico. Agradeço também à Dra. Lydia Yamamoto e Marta Canovas, que contribuíram para meu aprendizado ao longo do desenvolvimento deste trabalho. Ao Laboratório de Proteínas Musculares e Histopatologia Comparada do Centro de Estudos do Genoma Humano (GEGH) e ao Instituto de Biologia (IB) pelo inestimável auxílio e convivência. Aos professores, amigos e colegas pela dedicação e incentivo, auxílio, convívio, ensinamentos e amizade. Aos meus pais Olga e Abílio, minha irmã Ângela, meu sobrinho João Vitor e meu cunhado Raul pelo carinho, apoio e confiança. A Carolina pelo companheirismo, confiança, otimismo e alegrias. Aos meus "pais" Luiza e Edvaldo pelo carinho e pelas conversas sinceras. Aos meus queridos amigos Lucas, Priscila e Bruno pela amizade verdadeira, respeito e apoio em todas as ocasiões. Ao CNPq pelo auxílio financeiro que possibilitou o desenvolvimento dessa pesquisa. Enfim a todos que contribuíram para a realização deste trabalho. Muito obrigada! RESUMO LOPES, V. F. Caracterização funcional das diferentes linhagens de modelos murinos para distrofias musculares. 2010. 63 f. Dissertação (Mestrado em Biotecnologia)
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