LETICIA FERREIRA GONTIJO SILVEIRA
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
3 resultados
Resultados de Busca
Agora exibindo 1 - 3 de 3
conferenceObject Clinical Presentation of Klinefelter Syndrome and Other Causes of Hypergonadotropic Hypogonadism(2016) SCHNOLL, C.; RENCK, A. Covallero; LIMA, L. Guimaraes; MENDONCA, B. Bilharinho de; LATRONICO, A. C.; SILVEIRA, L. F. G.- Misfolding Ectodomain Mutations of the Lutropin Receptor Increase Efficacy of Hormone Stimulation(2016) CHARMANDARI, E.; GUAN, R.; ZHANG, M.; SILVEIRA, L. G.; FAN, Q. R.; CHROUSOS, G. P.; SERTEDAKI, A. C.; LATRONICO, A. C.; SEGALOFF, D. L.We demonstrate 2 novel mutations of the LHCGR, each homozygous, in a 46,XY patient with severe Leydig cell hypoplasia. One is a mutation in the signal peptide (p.Gln18_Leu19ins9; referred to here as SP) that results in an alteration of the coding sequence of the N terminus of the mature mutant receptor. The other mutation (p.G71R) is also within the ectodomain. Similar to many other inactivating mutations, the cell surface expression of recombinant human LHR(SP,G71R) is greatly reduced due to intracellular retention. However, we made the unusual discovery that the intrinsic efficacy for agonist-stimulated cAMP in the reduced numbers of receptors on the cell surface was greatly increased relative to the same low number of cell surface wild-type receptor. Remarkably, this appears to be a general attribute of misfolding mutations in the ectodomains, but not serpentine domains, of the gonadotropin receptors. These findings suggest that there must be a common, shared mechanism by which disparate mutations in the ectodomain that cause misfolding and therefore reduced cell surface expression concomitantly confer increased agonist efficacy to those receptor mutants on the cell surface. Our data further suggest that, due to their increased agonist efficacy, extremely small changes in cell surface expression of misfolded ectodomain mutants cause larger than expected alterations in the cellular response to agonist. Therefore, for inactivating LHCGR mutations causing ectodomain misfolding, the numbers of cell surface mutant receptors on fetal Leydig cells of 46,XY individuals exert a more exquisite effect on the relative severity of the clinical phenotypes than already appreciated.
conferenceObject A New GNRH1 Mutation in a Boy with Congenital Isolated Hypogonadotropic Hypogonadism(2016) LIMA, L. Guimaraes; MONTENEGRO, L. Ribeiro; LERARIO, A. Marcondes; NISHI, M.; MENDONCA, B. B.; LATRONICO, A. C.; SILVEIRA, L. Ferreira Gontijo