title: Somatic mutations affecting the selectivity filter of KCNJ5 are frequent in 2 large unselected collections of adrenal aldosteronomas.
abstract: Primary hyperaldosteronism, one cause of which is aldosterone-producing adenomas (APAs), may account for ≤5% 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 (1.61 cm [95% CI: 1.39-1.83 cm] versus 1.04 cm [95% CI: 0.91-1.17 cm]; P<0.0001) but with substantial overlap in size between genotypes. The APAs carrying a mutation, but not those without, also consistently lacked a postural aldosterone response, suggesting a physiologically distinct subtype. Hence, somatic KCNJ5 mutations are not restricted to large APAs (>2 cm), and their frequency in our unselected series suggests they are common and could be important in the molecular pathogenesis of many sporadic cases of APA.
authors.affiliation: Clinical Pharmacology Unit, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
authors.forename: Elena A B
authors.initials: EA
authors.lastname: Azizan
authors.forename: Meena
authors.initials: M
authors.lastname: Murthy
authors.forename: Michael
authors.initials: M
authors.lastname: Stowasser
authors.forename: Richard
authors.initials: R
authors.lastname: Gordon
authors.forename: Bartosz
authors.initials: B
authors.lastname: Kowalski
authors.forename: Shengxin
authors.initials: S
authors.lastname: Xu
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Brown
authors.forename: Kevin M
authors.initials: KM
authors.lastname: O'Shaughnessy
mesh_terms: D000236:Adenoma / Q000097:blood / Q000150:complications* / Q000235:genetics; D000310:Adrenal Gland Neoplasms / Q000097:blood / Q000150:complications* / Q000235:genetics; D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D000450:Aldosterone / Q000096:biosynthesis*; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D006929:Hyperaldosteronism / Q000097:blood / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011379:Prognosis
chemical_list: D004273:DNA, Neoplasm; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D000450:Aldosterone