Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism

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Rassi-Cruz, Marcela ^[1] ; Maria, Andrea G. ^[2] ; Faucz, Fabio R. ^[2] ; London, Edra ^[2] ; Vilela, Leticia A. P. ^[1] ; Santana, Lucas S. ^[1] ; Benedetti, Anna Flavia F. ^[1] ; Goldbaum, Tatiana S. ^[1] ; Tanno, Fabio Y. ^[3] ; Srougi, Vitor ^[3] ; Chambo, Jose L. ^[3] ; Pereira, Maria Adelaide A. ^[1] ; Cavalcante, Aline C. B. S. ^[4] ; Carnevale, Francisco C. ^[4] ; Pilan, Bruna ^[4] ; Bortolotto, Luiz A. ^[5] ; Drager, Luciano F. ^{[5, 6]} ; Lerario, Antonio M. ^{[1, 7]} ; Latronico, Ana Claudia ^[1] ; Fragoso, V, Maria Candida B. ; Mendonca, Berenice B. ^[8] ; Zerbini, Maria Claudia N. ^[9] ; Stratakis, Constantine A. ^[2] ; Almeida, Madson Q. ^{[8, 10]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Lab Hormonios & Genet Mol LIM 42, Fac Med, Hosp Clin, Serv Endocrinol & Metab, Sao Paulo - Brazil

^[2] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD - USA

^[3] Univ Sao Paulo, Hosp Clin, Serv Urol, Fac Med, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Hosp Clin, Inst Radiol InRad, Fac Med, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Inst Coracao InCor, Unidade Hipertensao, Fac Med, Sao Paulo - Brazil

^[6] Univ Sao Paulo, Hosp Clin, Disciplina Nefrol, Unidade Hipertensao, Fac Med, Sao Paulo - Brazil

^[7] Univ Michigan, Endocrinol Metab & Diabet, Ann Arbor, MI 48109 - USA

^[8] Fragoso, Maria Candida B., V, Univ Sao Paulo, Lab Hormonios & Genet Mol LIM 42, Fac Med, Hosp Clin, Serv Endocrinol & Metab, Sao Paulo - Brazil

^[9] Univ Sao Paulo, Div Anat Patol, Fac Med, Sao Paulo - Brazil

^[10] Fragoso, Maria Candida B., V, Univ Sao Paulo, Inst Canc Estado Sao Paulo ICESP, Serv Endocrinol, Fac Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Endocrine-Related Cancer; v. 28, n. 1, p. 1-13, JAN 2021.
• Citações Web of Science: 0

Resumo

Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, `sporadic' bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of gene tic etiologies of PA. (AU)

• Processo FAPESP: 17/13394-8 - Investigação genética por sequenciamento paralelo em larga escala do Hiperaldosteronismo Primário causado por Hiperplasia Cortical Unilateral ou Bilateral da suprarrenal
• Beneficiário: Marcela Rassi da Cruz
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 18/23470-6 - Investigação do papel das fosfodiesterases no hiperaldosteronismo primário causado por hiperplasia unilateral e bilateral da suprarrenal
• Beneficiário: Marcela Rassi da Cruz
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
• Processo FAPESP: 15/17049-8 - Investigação genética dos tumores do córtex da suprarrenal produtores de aldosterona por sequenciamento de nova geração
• Beneficiário: Madson Queiroz Almeida
• Modalidade de apoio: Auxílio à Pesquisa - Regular