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Genetic analysis and mechanisms of modulation of congenital hypopituitarism phenotype in different species


Hypopituitarism is the deficiency of 1 or more hormones produced by the pituitary gland and, in most congenital cases, is associated with short stature due to GH deficiency (GHD) in childhood, which can evolve with other hormonal deficiencies during development and linear growth. Molecular investigation of genes involved in pituitary embryogenesis in the past 2 decades led to the diagnosis in 15% of patients, with more frequent allelic pathogenic variants in the PROP1 gene that courses with multiple hormonal deficiency in humans, who are treated with appropriate hormones, reaching normal stature, without restoring fertility. This differs in the Ames mouse with spontaneous mutation in the Prop1 gene and in the zebrafish with prop1 gene knockout. The molecular diagnosis by large-scale sequencing proved to be limited, and the approach of making a pituitary gland through the induction of pluripotent stem cells from peripheral blood leukocytes followed by the differentiation into secretory strains that produce pituitary hormones, will allow the study of gene patterns differentially expressed leading to the combined hormonal deficiency phenotype. On the other hand, access to the pituitary gland of treated Ames mice, which show fertility restoration after hormonal treatment, as well as access to the pituitary gland of the zebrafish, which presents a knockout in the prop1 gene, which, after a period of growth retardation in the larval phases, recover the growth and fertility in adulthood similar to the wild, will allow the evaluation of compensation mechanisms with adequate functioning of the pituitary function, leading to phenotypic variability between different species (AU)

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