ARMC5 Mutations Are a Frequent Cause of Primary Macronodular Adrenal Hyperplasia

Autor(es):Mostrar menos -

Alencar, Guilherme Asmar ^[1] ; Lerario, Antonio Marcondes ^[1] ; Nishi, Mirian Yumie ^[1] ; de Paula Mariani, Beatriz Marinho ^[1] ; Almeida, Madson Queiroz ^[1] ; Tremblay, Johanne ^[2] ; Hamet, Pavel ^[2] ; Bourdeau, Isabelle ^[2] ; Nogueira Zerbini, Maria Claudia ^[3] ; Albergaria Pereira, Maria Adelaide ; Gomes, Gilberto Carlos ^[4] ; Rocha, Manoel de Souza ^[4] ; Chambo, Jose Luis ^[5] ; Lacroix, Andre ^[2] ; Mendonca, Berenice Bilharinho ^[1] ; Barisson Villares Fragoso, Maria Candida ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Hosp Clin, Unidade Suprarrenal, Lab Hormonios & Genet Mol LIM42, Disciplina Endocr, BR-05403900 Sao Paulo - Brazil

^[2] Univ Montreal, Ctr Hosp, Dept Med, Montreal, PQ H2W 1T8 - Canada

^[3] Univ Sao Paulo, Fac Med, Dept Patol, BR-05403900 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Med, Hosp Clin, Dept Radiol, BR-05403900 Sao Paulo - Brazil

^[5] Univ Sao Paulo, Fac Med, Dept Cirurgia, Disciplina Urol, BR-05403900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 99, n. 8, p. E1501-E1509, AUG 2014.
• Citações Web of Science: 45

Resumo

Context: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, usually characterized by functioning adrenal macronodules and increased cortisol production. Familial clustering of PMAH has been described, suggesting an inherited genetic cause for this condition. Objective: The aim of the present study was to identify the gene responsible for familial PMAH. Patients and Methods: Forty-seven individuals of a Brazilian family with PMAH were evaluated. A single-nucleotide polymorphism-based genome-wide linkage analysis followed by whole-exome sequencing were then performed in selected family members. Additionally, 29 other patients with PMAH and 125 randomly selected healthy individuals were studied to validate the genetic findings. Moreover, PMAH tissue was also analyzed through whole-exome sequencing, conventional sequencing, and microsatellite analysis. Results: A heterozygous germline variant in the ARMC5 gene (p.Leu365Pro) was identified by whole-exome sequencing in a candidate genomic region (16p11.2). Subsequently, the same variant was confirmed by conventional sequencing in all 16 affected family members. The variant was predicted to be damaging by in silico methods and was not found in available online databases or in the 125 selected healthy individuals. Seven additional ARMC5 variants were subsequently identified in 5 of 21 patients with apparently sporadic PMAH and in 2 of 3 families with the disease. Further molecular analysis identified a somatic mutational event in 4 patients whose adrenal tissue was available. Conclusions: Inherited autosomal dominant mutations in the ARMC5 gene are a frequent cause of PMAH. Biallelic inactivation of ARMC5 is consistent with its role as a potential tumor suppressor gene. (AU)

• Processo FAPESP: 10/12702-1 - Aspectos clínicos e moleculares da hiperplasia adrenocortical macronodular independente de ACTH em sua forma familial
• Beneficiário: Maria Candida Barisson Villares Fragoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular