title: Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism.
abstract: 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 mutation is indistinguishable from wild type. Although the functional substitutions are remote from the selectivity filter, they affect the inward-rectification, the ability of the KCNJ5 channels to conduct Na(+) currents and ATII-induced aldosterone release from the H295R cell line. Together these data suggest that germline variation in the KCNJ5 gene has a role to play in the common sporadic form as well as the much rarer syndromic forms of primary aldosteronism.
authors.affiliation: Clinical Pharmacology Unit, Department of Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom. kmo22@medschl.cam.ac.uk.
authors.forename: Meena
authors.initials: M
authors.lastname: Murthy
authors.forename: Shengxin
authors.initials: S
authors.lastname: Xu
authors.forename: Gianmichele
authors.initials: G
authors.lastname: Massimo
authors.forename: Martin
authors.initials: M
authors.lastname: Wolley
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gordon
authors.forename: Michael
authors.initials: M
authors.lastname: Stowasser
authors.forename: Kevin M
authors.initials: KM
authors.lastname: O'Shaughnessy
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000378:metabolism / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000450:Aldosterone / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D015331:Cohort Studies; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014982:Xenopus laevis
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D000450:Aldosterone
keywords: KCNJ5, potassium channel; adrenal cortex; mutation, missense; polymorphism, single nucleotide