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Investigation of novel genetic alterations associated with the pathogenesis of Aldosteronomas by exome sequencing

Grant number: 21/10101-5
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): November 01, 2021
Effective date (End): October 31, 2025
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Madson Queiroz Almeida
Grantee:Augusto Garcia Guimarães
Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated research grant:19/15873-6 - Investigation of new genetic, clinical and pathological aspects of endocrine arterial hypertension, AP.TEM


Primary Aldosteronism (PA) is the most common form of secondary Hypertension (HT), with a prevalence of approximately 20% in patients with resistant Hypertension. In the last decade, somatic Pathogenic Variantes (PVs) in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 genes, which are involved in maintaining intracellular ionic homeostasis and cell membrane potential, were described in 38%, 9.3%, 5.3% and 1.7% of Aldosterone-Producing Adenomas (APAs), respectively. All these PVs lead to the activation of calcium signaling, the major trigger for aldosterone production. Additionally, somatic activating PVs in exon 3 of CTNNB1 gene, which is involved in the adrenocortical development, were identified in approximately 5% of APAs. More recently, the germline p.V1951G CACNA1H variant was described in a PA patient with APA. Recently, we showed similar findings in a Brazilian cohort of APAs. In addition, we studied 11 patients with APA by exome sequencing (paired blood and tumor DNA - extracted from tumor tissue macroscopic selected by a pathologist after surgery) to investigate new genetic causes of PA caused by APAs. Interestingly, CACNA1I gene, which encodes the ± 1I subunit of Cav 3.3 channel, emerged as a new candidate gene for the pathogenesis of APAs. Recent evidence demonstrated that investigation of somatic alterations in Aldosteronomas should be guided by aldosterone synthase (CYP11B2) expression by immunostaining. This approach significantly increases the identification of PVs in Aldosteronomas. The specific aims of this project are: 1) to perform exome sequencing (paired blood and tumor DNA - extracted from CYP11B2 positive areas in the immunohistochemistry) in patients with PA and APAs without somatic PVs in KCNJ5, CACNA1D, ATP1A1, ATP2B3 e CTNNB1 genes; 2) to correlate the molecular findings with clinical data; 3) to conduct functional studies to investigate the selected variants in candidate genes. (AU)

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Scientific publications
(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)
FAGUNDES, GUSTAVO F. C.; FREITAS-CASTRO, FELIPE; SANTANA, LUCAS S.; AFONSO, ANA CAROLINE F.; PETENUCI, JANAINA; FUNARI, MARIANA F. A.; GUIMARAES, AUGUSTO G.; LEDESMA, FELIPE L.; PEREIRA, MARIA ADELAIDE A.; VICTOR, CAROLINA R.; et al. Evidence for a Founder Effect of SDHB Exon 1 Deletion in Brazilian Patients With Paraganglioma. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v. N/A, p. 10-pg., . (19/15873-6, 21/10101-5, 21/11240-9, 21/10363-0)

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