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

P rimary hyperaldosteronism (PA) is now recognized as a common, treatable, and potentially curable form of hypertension. In fact it may account for ≥10% of cases of what would previously have been labeled as essential hypertension.1,2 The excessive aldosterone production usually derives from either an aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. The balance between these 2 pathologies varies; however, in most recently published series, bilateral adrenal hyperplasia is about twice as common as APA. 3,4 Although the majority of PA is sporadic, there are monogenic familial forms of the condition (familial hyperaldosteronism types I, II, and III [FH-I, FH-II, and FH-III]). The molecular basis for FHI, glucocorticoid-remediable aldosteronism, has been well understood for >2 decades and involves a recombination event that places the aldosterone synthase enzyme, CYP11B2, under the control of ACTH. 5,6 In contrast, the molecular genetics for FHIII has been resolved recently with the discovery that they are caused by germline mutations that cluster in the selectivity filter of a potassium channel, KCNJ5. 7-9 These mutations affect the Na + permeability of the channel, which is thought to lead to depolarization of zona glomerulosa cells in the adrenal cortex thereby activating aldosterone release.Before the discovery of selectivity filter mutations in KCNJ5, this potassium channel was not even recognized as being expressed in the human adrenal gland. However, it is now known to be important in sporadic as well as the much rarer syndromic forms of PA, 10 with ≤40% of APAs carrying somatic mutations in the same KCNJ5 gene. 7,11 The coding sequence for KCNJ5 has been resequenced in a large collection of adrenal lesions (both APAs and non-APAs) without identifying further somatic mutations outside of the selectivity filter itself. 12However, we hypothesized that rare variants, in the form of See Editorial Commentary, pp 668-669Abstract-Primary aldosteronism (autonomous aldosterone production with suppressed renin) plays an important pathophysiological role in what has been previously labeled as essential hypertension. Besides the recently described germline mutations in the KCNJ5 potassium channel associated with familial primary aldosteronism, somatic mutations in the same channel have been identified within aldosterone-producing adenomas. In this study, we have resequenced the flanking and coding region of KCNJ5 in peripheral blood DNA from 251 white subjects with primary aldosteronism to look for rare variants that might be important for the pathophysiology of sporadic primary aldosteronism. We have identified 3 heterozygous missense mutations (R52H, E246K, and G247R) in the cohort and found that 12 (5% of the cohort) were carriers for the rare nonsynonymous single nucleotide polymorphism rs7102584 causing E282Q substitution of KCNJ5. By expressing the channels in Xenopus oocytes and human adrenal H295R cells, we have shown that the R52H, E246K, and E282Q substitutions are functional, but the G247R...