Advances in the understanding of the pathophysiology of primary adrenocortical hyperplasia macronodular - PMAH (GP-PMAH)

• Grant number: 15/50192-9
• Support Opportunities: Research Projects - Thematic Grants
• Start date: February 01, 2016
• End date: September 30, 2019
• Field of knowledge: Health Sciences - Medicine
• Agreement: ANR
• Principal Investigator: Maria Candida Barisson Villares Fragoso
• Grantee: Maria Candida Barisson Villares Fragoso
• Principal researcher abroad: Jérôme Yves Bertherat
• Institution abroad: Université Paris Descartes - Paris 5, France
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Claudimara Ferini Pacicco Lotfi ; Mirian Yumie Nishi
• Associated scholarship(s): 17/11495-1 - Primary Macronodular Adrenocortical Hyperplasia: morphological, immunohistochemical study and its correlation with genetic-molecular alterations, BP.DD; 15/06146-2 - The frequency of ARMC5 Mutation in incidental nodules in the adrenal gland associated with subclinical hypercortisolism, BP.DR

Abstract

Cushing syndrome (CS) results from chronic excess of cortisol production and represents and archetype of metabolic syndrome (MS). The MS is a condition defined as a complex of interconnected cardiovascular risk factors such as (obesity, diabetes, blood hypertension and dyslipidemia). It is estimated that 2/3 of CS patients fulfill the criteria for MS. PMAH is a cause of CS, usually diagnosed in 5th or 6th decades. The duration of exposure of cortisol excess and affinity to its receptor are determinant of cardiovascular risk. The mortality is higher among patients who have not received effective treatment for hypercortisolism than the patients who are cured thus there is a clinical imperative for early diagnosis and treatment. Last year the group from Prof. Jérôme Bertherat (France) and the group from Prof. Maria CBV Fragoso (Brazil), using different molecular approaches identified the gene related to PMAH, the ARMC5 (armadillo repeat containing 5). Germline mutations of ARMC5 were identified around 55% if familial cases and in 21% of sporadic cases. The unique functional study of ARMC5 was conducted by the France group in cell culture of adrenal cancer (NCI). The authors observed the apoptotic effect of the wide type of ARMC5. Our group have stored a bank of hyperplastic adrenal tissue (in liquid nitrogen – 180C) and their cell cultures respectively from patients with PMAH. This is opportunity to develop a collaborative study to characterize the culture cells of PMAH and perform new functional studies in these cells with and without ARMC5 mutations. (AU)

Scientific publications

(8)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BARISSON VILLARES FRAGOSO, MARIA CANDIDA; CAVALCANTE, ISADORA PONTES; FERREIRA, AMANDA MENESES; DE PAULA MARIANI, BEATRIZ MARINHO; PACICCO LOTFI, CLAUDIMARA FERINI. Genetics of primary macronodular adrenal hyperplasia. PRESSE MEDICALE, v. 47, n. 7-8, 2, SI, p. E139-E149, JUL-AUG 2018. (15/50192-9)

TANNO, FABIO YOSHIAKI; SROUGI, VICTOR; ALMEIDA, MADSON Q.; YAMAUCHI, FERNANDO IDE; ALMEIDA COELHO, FERNANDO MORBECK; NISHI, MIRIAN YUMIE; NOGUEIRA ZERBINI, MARIA CLAUDIA; CORREA SOARES, IRACY SILVIA; ALBERGARIA PEREIRA, MARIA ADELAIDE; SILVA CHARCHAR, HELAINE LAIZ; et al. A New Insight into the Surgical Treatment of Primary Macronodular Adrenal Hyperplasia. JOURNAL OF THE ENDOCRINE SOCIETY, v. 4, n. 8, AUG 2020. (15/50192-9)

CAVALCANTE, ISADORA P.; NISHI, MIRIAN; ZERBINI, MARIA CLAUDIA N.; ALMEIDA, MADSON Q.; BRONDANI, VANIA B.; ANHAIA DE ARRUDA BOTELHO, MARIA LUIZA; TANNO, FABIO Y.; SROUGI, VICTOR; CHAMBO, JOSE LUIS; MENDONCA, BERENICE B.; et al. The role of ARMC5 in human cell cultures from nodules of primary macronodular adrenocortical hyperplasia (PMAH). Molecular and Cellular Endocrinology, v. 460, n. C, p. 36-46, JAN 15 2018. (15/50192-9)

MARIANI, BEATRIZ MARINHO DE PAULA; NISHI, MIRIAN YUMIE; WANICHI, INGRID QUEVEDO; BRONDANI, VANIA BALDERRAMA; LACOMBE, AMANDA MENESES FERREIRA; CHARCHAR, HELAINE; PEREIRA, MARIA ADELAIDE ALBERGARIA; SROUGI, VICTOR; TANNO, FABIO YOSHIAKI; CECCATO, FILIPPO; et al. Allelic Variants of ARMC5 in Patients With Adrenal Incidentalomas and in Patients With Cushing's Syndrome Associated With Bilateral Adrenal Nodules. FRONTIERS IN ENDOCRINOLOGY, v. 11, FEB 7 2020. (15/06146-2, 15/50192-9)

CAVALCANTE, ISADORA PONTES; VACZLAVIK, ANNA; DROUGAT, LUDIVINE; PACICCO LOTFI, CLAUDIMARA FERINI; HECALE-PERLEMOINE, KARINE; RIBES, CHRISTOPHER; RIZK-RABIN, MARTHE; CLAUSER, ERIC; BARISSON VILLARES FRAGOSO, MARIA CANDIDA; BERTHERAT, JEROME; et al. CuIlin 3 targets the tumor suppressor gene ARMC5 for ubiquitination and degradation. Endocrine-Related Cancer, v. 27, n. 4, p. 221-230, APR 2020. (15/50192-9)

BARISSON VILLARES FRAGOSO, MARIA CANDIDA; CAVALCANTE, ISADORA PONTES; FERREIRA, AMANDA MENESES; DE PAULA MARIANI, BEATRIZ MARINHO; PACICCO LOTFI, CLAUDIMARA FERINI. Genetics of primary macronodular adrenal hyperplasia. PRESSE MEDICALE, v. 47, n. 7-8, p. 11-pg., 2018-07-01. (15/50192-9)

CAVALCANTE, ISADORA P.; BERTHON, ANNABEL; FRAGOSO, MARIA C.; REINCKE, MARTIN; STRATAKIS, CONSTANTINE A.; RAGAZZON, BRUNO; BERTHERAT, JEROME. Primary bilateral macronodular adrenal hyperplasia: definitely a genetic disease. NATURE REVIEWS ENDOCRINOLOGY, v. 18, n. 11, p. 13-pg., 2022-08-03. (15/50192-9)

BARBARA BRITO DA CONCEIÇÃO; ISADORA PONTES CAVALCANTE; JEAN LUCAS KREMER; THAIS BARABBA AURICINO; EDUARDA CORRÊA BENTO; MARIA CLAUDIA NOGUEIRA ZERBINI; MARIA CANDIDA BARISSON VILLARES FRAGOSO; CLAUDIMARA FERINI PACICCO LOTFI. ARMC5 mutations are associated with high levels of proliferating cell nuclear antigen and the presence of the serotonin receptor 5HT4R in PMAH nodules. ARCHIVES OF ENDOCRINOLOGY METABOLISM, v. 64, n. 4, p. 390-401, 2020-04-06. (15/50192-9, 15/14199-9)