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Investigation of phosphodiesterases role in primary aldosteronism caused by unilateral and bilateral adrenal hyperplasia

Grant number: 18/23470-6
Support type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): March 11, 2019
Effective date (End): May 10, 2019
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Madson Queiroz Almeida
Grantee:Marcela Rassi da Cruz
Supervisor abroad: Constantine A Stratakis
Home Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Local de pesquisa : National Institutes of Health, Bethesda (NIH), United States  
Associated to the scholarship:17/13394-8 - Genetic investigation by next generation sequencing of Primary Aldosteronism caused by Unilateral or Bilateral Adrenal Hyperplasia, BP.DD

Abstract

Primary aldosteronism (PA) is the most common form of secondary hypertension, with a prevalence of approximately 20% in patients with resistant hypertension. In the last decade, considerable advances have been made towards the better understanding of PA genetics. Somatic pathogenic variations 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 tumors, respectively. Somatic activating variants in exon 3 of CTNNB1 gene, involved in the adrenocortical development, were also identified in 3 tumors. Among familial PA, germlines defects in KCNJ5, CACNA1D and CACNA1H were identified in PA patients diagnosed before 10 years of age. However, genetic factors involved in the pathogenesis of PA caused by unilateral and bilateral adrenal hyperplasia in adults remains poorly elucidated. We excluded by Sanger automated sequencing hot spot somatic mutations in aldosterone-driver genes (KCNJ5, ATP1A1, ATP2B3 and CTNNB1) in 7 unilateral and 7 bilateral adrenal hyperplasia from PA patients. Then we performed whole exome sequencing (paired blood and tissue) of the patients without somatic mutations in the previously described genes. After exome bioinformatics analysis, we found novel and rare germline variants in the phosphodiesterases genes PDE2A, PDE1A and PDE3B in patients with PA caused by unilateral and bilateral hyperplasia. All variants were predicted to be pathogenic in silico. Although PDE11A and PDE6B were already associated with Cushing syndrome and micronodular bilateral hyperplasia, the PDE involvement in PA pathogenesis is new and probably relevant. The aim of this collaborative project is to conduct functional studies to better characterize PDE role in PA. To achieve this goal, we will collaborate with a laboratory with expertise in cAMP and PDE signaling.