• Home
  • Search Results
  • ARMC5 mutations are a frequent cause of primary macronodular adrenal Hyperplasia.

ARMC5 mutations are a frequent cause of primary macronodular adrenal Hyperplasia.

The Journal of clinical endocrinology and metabolism (2014-04-09)
Guilherme Asmar Alencar, Antonio Marcondes Lerario, Mirian Yumie Nishi, Beatriz Marinho de Paula Mariani, Madson Queiroz Almeida, Johanne Tremblay, Pavel Hamet, Isabelle Bourdeau, Maria Claudia Nogueira Zerbini, Maria Adelaide Albergaria Pereira, Gilberto Carlos Gomes, Manoel de Souza Rocha, Jose Luis Chambo, André Lacroix, Berenice Bilharinho Mendonca, Maria Candida Barisson Villares Fragoso
ABSTRACT

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. The aim of the present study was to identify the gene responsible for familial PMAH. 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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Dichloromethane, anhydrous, ≥99.8%, contains 40-150 ppm amylene as stabilizer
Sigma-Aldrich
Dichloromethane, suitable for HPLC, ≥99.8%, contains amylene as stabilizer
Sigma-Aldrich
Dichloromethane, contains 40-150 ppm amylene as stabilizer, ACS reagent, ≥99.5%
Sigma-Aldrich
Hydrocortisone, BioReagent, suitable for cell culture
Sigma-Aldrich
Dichloromethane, HPLC Plus, for HPLC, GC, and residue analysis, ≥99.9%, contains 50-150 ppm amylene as stabilizer
Sigma-Aldrich
Dichloromethane, puriss. p.a., ACS reagent, reag. ISO, ≥99.9% (GC)
Sigma-Aldrich
Hydrocortisone, ≥98% (HPLC)
Sigma-Aldrich
Hydrocortisone, γ-irradiated, powder, BioXtra, suitable for cell culture
Supelco
Methylene Chloride, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Dichloromethane, suitable for HPLC, ≥99.9%, contains 40-150 ppm amylene as stabilizer
Supelco
Hydrocortisone, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Dichloromethane, analytical standard
Sigma-Aldrich
Dichloromethane, puriss., meets analytical specification of Ph. Eur., NF, ≥99% (GC)
Sigma-Aldrich
Dichloromethane, ACS reagent, ≥99.5%, contains 40-150 ppm amylene as stabilizer
Hydrocortisone, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Dichloromethane, ACS reagent, ≥99.5%, contains 40-150 ppm amylene as stabilizer
USP
Hydrocortisone, United States Pharmacopeia (USP) Reference Standard
Methylene chloride, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Hydrocortisone, meets USP testing specifications
Supelco
Dichloromethane solution, certified reference material, 200 μg/mL in methanol
Hydrocortisone for peak identification, European Pharmacopoeia (EP) Reference Standard
Supelco
Dichloromethane, analytical standard, stabilized
Supelco
Dichloromethane solution, certified reference material, 5000 μg/mL in methanol
Supelco
Dichloromethane, Selectophore, ≥99.5%
Sigma-Aldrich
Dichloromethane, biotech. grade, 99.9%, contains 40-150 ppm amylene as stabilizer
Supelco
Hydrocortisone, VETRANAL®, analytical standard
Hydrocortisone, British Pharmacopoeia (BP) Assay Standard
Supelco
Dichloromethane solution, contains 10 % (v/v) methanol
Supelco
Dichloromethane, ≥99.9%