Somatic Mutations Affecting the Selectivity Filter of KCNJ5 Are Frequent in 2 Large Unselected Collections of Adrenal Aldosteronomas

Abstract

Abstract-Primary hyperaldosteronism, one cause of which is aldosterone-producing adenomas (APAs), may account for Յ5% to 10% of cases of essential hypertension. Germline mutations have been identified in 2 rare familial forms of primary hyperaldosteronism, but it has been reported recently that somatic mutations of the KCNJ5 gene, which encodes a potassium channel, are present in some sporadic nonsyndromic APAs. To address this further we screened 2 large collections of sporadic APAs from the United Kingdom and Australia (totalling 73) and found somatic mutations in the selectivity filter of KCNJ5 in 41% (95% CI: 31% to 53%) of the APAs (30 of 73). These included the previously noted nonsynonymous mutations, G151R and L158R, and an unreported 3-base deletion, delI157, in the region of the selectivity filter. APAs containing a somatic KCNJ5 mutation were significantly larger than those without ( Key Words: hyperaldosteronism Ⅲ hypertension Ⅲ potassium channels Ⅲ KCNJ5 Ⅲ aldosterone-producing adenoma Ⅲ posture response P rimary hyperaldosteronism (PA) is now recognized as a common, treatable, and potentially curable form of hypertension, which may account for Յ10% of cases of socalled essential hypertension. [1][2][3] Most cases of PA are sporadic and result from 2 major types of adrenal pathology, an aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. In recently published series, the frequency of APA varied between 28% and 50% of patients with PA. 4 Choi et al 5 recently reported somatic mutations in a potassium channel, KCNJ5 (also called GIRK4 or Kir3.4), in 8 of 20 APAs studied and a germline mutation in the same gene in all 3 affected members of a family with florid, early onset, nondexamethasone-suppressible PA associated with marked hyperplasia of zona fasciculata (ZF), suggesting a novel pathway that might activate growth of aldosteronesecreting cells. These mutations within the selectivity filter of the potassium channel reduce the normal K ϩ /Na ϩ selectivity of the channel, and the resulting depolarization of the adrenocortical cell could lead to calcium loading and growth. However, the APAs carrying KCNJ5 mutations were large (mean of 2.8 cm and all Ͼ2 cm in diameter) and might represent a subgroup with a phenotype more relevant to the giant hyperplastic adrenals seen in the family with the germline KCNJ5 mutation. 5 To address this issue we have screened a large collection of APAs (totalling 73) from geographically distinct centers (United Kingdom and Australia) to determine whether somatic mutations of KCNJ5 are present in unselected APAs regardless of size. We also

KCNJ5 mutations in aldosterone- and cortisol-co-secreting adrenal adenomas [Rapid Communication]

“…We found mutations of the KCNJ5 gene in 15 of 23 (about 65%) APAs in Japan, and Azizan et al reported a lower frequency, 38% in Australia and 44% in the United Kingdom [11,12]. Boulkroun et al examined the largest number, 380 cases of APA, and found that 34% patients had mutations in Europe [13].…”

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

“…To assess whether APCCs harbored somatic mutations seen in APA, we developed a custom Ion Torrent AmpliSeq Panel (APA_v1) with 310 multiplexed amplicons targeting the entire coding sequences of genes with described somatic mutations in APA (ATP1A1, ATP2B3, CACNA1D, and KCNJ5) as well as genes shown to harbor germ-line or somatic variants associated with adrenal hyperplasia [phosphodiesterase 11A (PDE11A), phosphodiesterase 8B (PDE8B), and protein kinase, cAMP-dependent, regulatory, type Iα (PRKAR1A)] (7,10,13,(18)(19)(20)(21)(22)(23)(24)(25)(26). NGS was performed on APCCs and paired control adrenal tissue (adjacent ZF and/or medulla), both of which were isolated from formalin-fixed, paraffin-embedded (FFPE) adrenal samples (marked P in Table 1).…”

“…The custom Ion AmpliSeq Panel was designed to target genes previously shown to be mutated in APA or other adrenal hyperplasias/ neoplasms (APA_v1 Panel). The APA_v1 Panel contains 310 independent pairs of forward and reverse primers targeting the entire coding regions of ATP1A1, ATB2B3, KCNJ5, and CACNA1D as well as genes shown to harbor germ-line or somatic variants associated with adrenal hyperplasia (PDE11A, PDE8B, and PRKAR1A) (7,10,13,(18)(19)(20)(21)(22)(23)(24)(25)(26). Templates were prepared using the Ion PI Template OT2 200 Kit v2 on the Ion One Touch 2 according to the manufacturer's instructions (Life Technologies).…”

Clinical Characteristics of Somatic Mutations in Chinese Patients With Aldosterone-Producing Adenoma

“…10,13,14,[18][19][20][21][22] First, somatic KCNJ5 mutations were more common in female than male patients. Second, in the presence of KCNJ5 mutations, larger tumor size, higher urinary aldosterone, higher aldosterone-renin ratio, and lateralization index were observed, which suggested that excess aldosterone was related to the mutated APA.…”