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Molecular mechanisms of ARMC5 mutations in adrenal pathophysiology.

ABSTRACT: Since the initial discovery of mutations in the Armadillo-containing repeat protein 5 gene (ARMC5) in primary bilateral macronodular adrenocortical hyperplasia (PBMAH), efforts have been made to better understand the molecular mechanisms involving ARMC5 in the development of this rare form of Cushing syndrome. It has now been established that germline ARMC5-inactivating mutations, mostly frameshift and nonsense ones, are responsible for roughly 40% of PBMAH cases. ARMC5 is a tumor suppressor gene responsible for a familial form of PBMAH. Furthermore, the presence of inactivating ARMC5 mutations is associated with a more severe CS and hypertension as well as an overall increase in adrenal mass. However, ARMC5 inactivation decreases cortisol secretion both in vitro and in vivo (in mice) suggesting that the way that ARMC5 deficiency leads to Cushing syndrome is complicated and maybe not a direct effect of the ARMC5's loss, requiring additional molecular events to take place. Moreover, in silico predicted damaging ARMC5 variants have been identified in patients of African American descent with primary aldosteronism suggesting a potential role of ARMC5 in predisposing to low renin hypertension. Beyond its role in adrenocortical cells, ARMC5 defects has recently been associated with meningioma and T-cell immune response defects in humans and mice, respectively. Herein, we review recent discoveries in ARMC5's role in adrenal pathophysiology and beyond; clearly, we are only at the beginning of understanding the function of this gene with functions in the adrenal gland, the immune system, and elsewhere.

SUBMITTER: Stratakis CA

PROVIDER: S-EPMC7448540 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Molecular mechanisms of ARMC5 mutations in adrenal pathophysiology.

Stratakis Constantine A CA Berthon Annabel A

Current opinion in endocrine and metabolic research 20190809

Since the initial discovery of mutations in the Armadillo-containing repeat protein 5 gene (ARMC5) in primary bilateral macronodular adrenocortical hyperplasia (PBMAH), efforts have been made to better understand the molecular mechanisms involving ARMC5 in the development of this rare form of Cushing syndrome. It has now been established that germline ARMC5-inactivating mutations, mostly frameshift and nonsense ones, are responsible for roughly 40% of PBMAH cases. ...[more]

PMID: 32864505

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Project description:Objective: Germline ARMC5 mutations are considered to be the main genetic cause of primary macronodular adrenal hyperplasia (PMAH). PMAH is associated with high variability of cortisol secretion caused from subclinical hypercortisolism to overt Cushing's syndrome (CS), in general due to bilateral adrenal nodules and rarely could also be due to non-synchronic unilateral adrenal nodules. The frequency of adrenal incidentalomas (AI) associated with PMAH is unknown. This study evaluated germline allelic variants of ARMC5 in patients with bilateral and unilateral AI and in patients with overt CS associated with bilateral adrenal nodules. Methods: We performed a retrospective multicenter study involving 123 patients with AI (64 bilateral; 59 unilateral). We also analyzed 20 patients with ACTH pituitary independent overt CS associated with bilateral adrenal nodules. All patients underwent germline genotyping analysis of ARMC5; abdominal CT and were classified as normal, possible or autonomous cortisol secretion, according to the low doses of dexamethasone suppression test. Results: We identified only one pathogenic allelic variant among the patients with bilateral AI. We did not identify any pathogenic allelic variants of ARMC5 in patients with unilateral AI. Thirteen out of 20 patients (65%) with overt CS and bilateral adrenal nodules were carriers of pathogenic germline ARMC5 allelic variants, all previously described. The germline ARMC5 mutation was observed in only one patient with bilateral AI; it was associated with autonomous cortisol secretion and showed to be a familial form. Conclusion: The rarity of germline ARMC5 mutations in AI points to other molecular mechanisms involved in this common adrenal disorder and should be investigated. In contrast, patients with overt Cushing's syndrome and bilateral adrenal nodules had the presence of ARMC5 mutations that were with high prevalence and similar to the literature. Therefore, we recommend the genetic analysis of ARMC5 for patients with established Cushing's syndrome and bilateral adrenal nodules rather than patients with unilateral AI.

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Molecular mechanisms of ARMC5 mutations in adrenal pathophysiology.

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Molecular mechanisms of <i>ARMC5</i> mutations in adrenal pathophysiology.

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