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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Mineralocorticoid Receptor Mutations Differentially Affect Individual Gene Expression Profiles in Pseudohypoaldosteronism Type 1

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Autor(es):
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Fernandes-Rosa, Fabio L. [1, 2, 3] ; Hubert, Edwige-Ludiwyne [1, 2] ; Fagart, Jerome [4, 5] ; Tchitchek, Nicolas [6] ; Gomes, Debora [3] ; Jouanno, Elodie [2, 7] ; Benecke, Arndt [6] ; Rafestin-Oblin, Marie-Edith [8, 9] ; Jeunemaitre, Xavier [1, 2, 7] ; Antonini, Sonir R. [3] ; Zennaro, Maria-Christina [1, 2, 7]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Paris Cardiovasc Res Ctr PARCC, INSERM, U970, F-75015 Paris - France
[2] Univ Paris 05, F-75005 Paris - France
[3] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Puericulture & Pediat, BR-14040900 Ribeirao Preto - Brazil
[4] Hop Bicetre, INSERM, U693, F-94270 Le Kremlin Bicetre - France
[5] Univ Paris Sud, F-94270 Le Kremlin Bicetre - France
[6] Inst Hautes Etud Sci, F-91440 Bures Sur Yvette - France
[7] Hop Europeen Georges Pompidou, AP HP, F-75015 Paris - France
[8] Ctr Rech Biomed Bichat Beaujon CRB3, INSERM, U773, F-75870 Paris - France
[9] Univ Paris Diderot, F-75475 Paris - France
Número total de Afiliações: 9
Tipo de documento: Artigo Científico
Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 96, n. 3, p. E519-E527, MAR 2011.
Citações Web of Science: 15
Resumo

Context: Type 1 pseudohypoaldosteronism (PHA1), a primary form of mineralocorticoid resistance, isdueto inactivating mutations of the NR3C2 gene, coding for the mineralocorticoid receptor (MR). Objective: The objective of the study was to assess whether different NR3C2 mutations have distinct effects on the pattern of MR-dependent transcriptional regulation of aldosterone-regulated genes. Design and Methods: Four MR mutations affecting residues in the ligand binding domain, identified in families with PHA1, were tested. MR proteins generated by site-directed mutagenesis were analyzed for their binding to aldosterone and were transiently transfected into renal cells to explore the functional effects on the transcriptional activity of the receptors by cis-trans-cotrans-activation assays and by measuring the induction of endogenous gene transcription. Results: Binding assays showed very low or absent aldosterone binding for mutants MR(877Pro), MR(848Pro), and MR(947stop) and decreased affinity for aldosterone of MR(843Pro). Compared with wildtype MR, the mutations p.Leu843Pro and p.Leu877Pro displayed half-maximal aldosterone-dependent transactivation of reporter genes driven by mouse mammary tumor virus or glucocorticoid response element-2 dependent promoters, whereas MR(848Pro) and MR(947stop) nearly or completely lost transcriptional activity. Although MR(848Pro) and MR(947stop) were also incapable of inducing aldosterone-dependent gene expression ofendogenoussgk1, GILZ, NDRG2, and SCNN1A, MR(843Pro) retained complete transcriptional activity on sgk1 and GILZ gene expression, and MR(877Pro) negatively affected the expression of sgk1, NDRG2, and SCNN1A. Conclusions: Our data demonstrate that MR mutations differentially affect individual gene expression in a promoter-dependent manner. Investigation of differential gene expression profiles in PHA1 may allow a better understanding of the molecular substrate of phenotypic variability and to elucidate pathogenic mechanisms underlying the disease. (J Clin Endocrinol Metab 96: E519-E527, 2011) (AU)

Processo FAPESP: 05/59495-2 - Estudo funcional das mutações r947x e l848p e estudo de efeito fundador da mutação r947x no gene do receptor do mineralocorticóide em famílias com a forma renal do pseudohipoaldosteronismo tipo 1
Beneficiário:Fabio Luiz Fernandes Rosa
Linha de fomento: Bolsas no Brasil - Doutorado