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  • Author: Maria Candida B V Fragoso x
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Marcela Rassi-Cruz Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Andrea G Maria Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA

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Fabio R Faucz Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA

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Edra London Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA

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Leticia A P Vilela Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Lucas S Santana Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Anna Flavia F Benedetti Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Tatiana S Goldbaum Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Fabio Y Tanno Serviço de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Vitor Srougi Serviço de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Jose L Chambo Serviço de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Maria Adelaide A Pereira Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Aline C B S Cavalcante Instituto de Radiologia InRad, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Francisco C Carnevale Instituto de Radiologia InRad, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Bruna Pilan Instituto de Radiologia InRad, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Luiz A Bortolotto Unidade de Hipertensão, Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Luciano F Drager Unidade de Hipertensão, Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Unidade de Hipertensão, Disciplina de Nefrologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Antonio M Lerario Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Endocrinology, Metabolism and Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Ana Claudia Latronico Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Maria Candida B V Fragoso Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Servico de Endocrinologia, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Berenice B Mendonca Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Maria Claudia N Zerbini Divisão de Anatomia Patológica, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Constantine A Stratakis Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA

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Madson Q Almeida Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Servico de Endocrinologia, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Abstract

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 genetic etiologies of PA.

Article Type:
Research Article
DOI:
https://doi.org/10.1530/ERC-20-0384
Volume/Issue:
Volume 28: Issue 1
Restricted access
Tomoko Sekiya Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Marcello D Bronstein Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Katiuscia Benfini Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Viviane C Longuini Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Raquel S Jallad Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Marcio C Machado Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Tatiana D Goncalves Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Luciana H Osaki Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Leonardo Higashi Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Jose Viana-Jr Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil
Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Claudio Kater Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Misu Lee Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Sara Molatore Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Guilherme Francisco Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Roger Chammas Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Michel S Naslavsky Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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David Schlesinger Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil
Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Patricia Gama Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Yeda A O Duarte Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Maria Lucia Lebrão Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Mayana Zatz Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Osorio Meirelles Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Bernardo Liberman Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Maria Candida B V Fragoso Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Sergio P A Toledo Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Natalia S Pellegata Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Rodrigo A Toledo Endocrine Genetics Unit LIM-25, Neuroendocrinology Unit, Adrenal Unit (LIM-42), Experimental Oncology Laboratory (LIM-24), Nursing School, School of Public Health, Endocrinology Division, Brigadeiro Hospital, Federal University of Sao Paulo, Human Genome Research Center, Department of Cell and Developmental Biology, Instituto do Cérebro, National Institute of Aging, Institute of Pathology, School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil

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Abstract

Germline mutations in p27 kip1 are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, n=252; pheochromocytomas, n=125; medullary thyroid carcinoma, n=51; and parathyroid adenomas, n=19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (P=0.01), particularly for those with ACTH-secreting pituitary adenomas (P=0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with the sporadic counterpart of MEN2-component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27-V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far.

Article Type:
Research Article
DOI:
https://doi.org/10.1530/ERC-13-0486
Volume/Issue:
Volume 21: Issue 3
Free access