ARMC5 mutation analysis in patients with primary aldosteronism and bilateral adrenal lesions

Abstract

Idiopathic hyperaldosteronism (IHA) due to bilateral adrenal hyperplasia is the most common subtype of primary aldosteronism (PA). The pathogenesis of IHA is still unknown, but the bilateral disease suggests a potential predisposing genetic alteration. Heterozygous germline mutations of armadillo repeat containing 5 (ARMC5) have been shown to be associated with hypercortisolism due to sporadic primary bilateral macronodular adrenal hyperplasia and are also observed in African-American PA patients. We investigated the presence of germline ARMC5 mutations in a group of PA patients who had bilateral computed tomography-detectable adrenal alterations. We sequenced the entire coding region of ARMC5 and all intron/exon boundaries in 39 patients (37 Caucasians and 2 black Africans) with confirmed PA (8 unilateral, 27 bilateral and 4 undetermined subtype) and bilateral adrenal lesions. We identified 11 common variants, 5 rare variants with a minor allele frequency <1% and 2 new variants not previously reported in public databases. We did not detect by in silico analysis any ARMC5 sequence variations that were predicted to alter protein function. In conclusion, ARMC5 mutations are not present in a fairly large series of Caucasian patients with PA associated to bilateral adrenal disease. Further studies are required to definitively clarify the role of ARMC5 in the pathogenesis of adrenal nodules and aldosterone excess in patients with PA.

GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

“…Page 10 of 31 study failed to confirm this association in patients of European ancestry (42). Similarly, a potential role of ARMC5 in FH-II has been recently ruled out (43).…”

Evolution of computed tomography-detectable adrenal nodules in patients with bilateral primary aldosteronism

“…Malignant transformation has been reported in incidentally found non-functioning adrenal adenomas [11], and several mitogenic factors are known to control adrenal growth and aldosterone secretion in unilateral/bilateral aldosteronism [12]. Our CT data showed that adrenal mass enlargement in no case exceeded 3 cm of diameter or was associated with signs of malignant transformation, suggesting that mass increase was casual and not a marker of malignancy.…”

Genetics of primary hyperaldosteronism

“…Furthermore, overexpression of mutant ARMC5 was found to downregulate CYP11B2 expression. Recently, Mulatero and coworkers also reported ARMC5 mutations in Caucasian patients (Mulatero et al 2016). They identified 18 variants of ARMC5.…”