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Cited by 162Adrenal and Paraganglionic TumorsAdrenal Hormones and DisordersPituitary Gland Disorders and Treatments

ARMC5 Mutations Are a Frequent Cause of Primary Macronodular Adrenal Hyperplasia

Alencar, Guilherme Asmar, Lerario, Antonio Marcondes, Nishi, Mirian Yumie, Mariani, Beatriz Marinho de Paula, Almeida, Madson Queiroz, Tremblay, Johanne, Hamet, Pavel, Bourdeau, Isabelle +8 more·2014·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2013-4237
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Abstract

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.

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  • Patients with ARMC5 mutations tend to display adrenal hyperplasia associated with multiple nodules.

    “Patients with ARMC5 mutations tend to display adrenal hyperplasia associated with multiple nodules (172-175).”

    From Adrenal incidentaloma (2020) · cites this paper as [172]

  • The penetrance of ARMC5 mutations is variable.

    “The penetrance of ARMC5 mutations is variable (172).”

    From Adrenal incidentaloma (2020) · cites this paper as [172]

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Authors
Alencar, G. A., Lerario, A. M., Nishi, M. Y., Mariani, B. M. D. P., Almeida, M. Q., Tremblay, J., Hamet, P., Bourdeau, I., Zerbini, M. C. N., Pereira, M. A. A., Gomes, G. C., Rocha, M. D. S., Chambo, J. L., Lacroix, A., Mendonca, B. B., & Fragoso, M. C. B. V.
Affiliations
  • Universidade de São Paulo (BR)
  • Unidade de Suprarrenal (G.A.A., A.M.L., M.Y.N., B.M.d.P.M., M.Q.A., M.A.A.P., B.B.M., M.C.B.V.F.), Disciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403900, Brazil
  • Centre Hospitalier de l’Université de Montréal (CA)
  • Departamento de Patologia (M.C.N.Z.), Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403900, Brazil
Corresponding author
  • Alencar, Guilherme Asmar
  • Fragoso, Maria Candida Barisson Villares
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2014-08-01
Volume
99
Issue
8
Pages
E1501-E1509
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2013-4237
OpenAlex
W2165231206
Cited by
162
References
40
Citations by year
2026: 10 · 2025: 8 · 2024: 14 · 2023: 10 · 2022: 18 · 2021: 9 · 2020: 15 · 2019: 10 · 2018: 16 · 2017: 11 · 2016: 12 · 2015: 18 · 2014: 9
FWCI
16.50
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
Keywords
ARMC5, Cushing's syndrome, germline mutations, autosomal dominant inheritance, familial aggregation, tumor suppressor, 16p11.2, somatic mutations
MeSH terms
Adult, Aged, Aged, 80 and over, Brazil, Cushing Syndrome, Female, Gene Frequency, Humans, Genetic Linkage, Male, Middle Aged, Pedigree, Germ-Line Mutation, Genetic Predisposition to Disease, Mutation, Missense, Tumor Suppressor Proteins, Armadillo Domain Proteins

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