title: New insights into aldosterone-producing adenomas and hereditary aldosteronism:  mutations in the K+ channel KCNJ5.
abstract: OBJECTIVE
  Primary aldosteronism is a major cause of secondary hypertension worldwide. This review describes the recent studies that have provided dramatic new insight into the pathogenesis of aldosterone-producing adenomas (APAs) and inherited primary aldosteronism, revealing the role of mutations in the potassium channel KCNJ5 in these disorders.
  
  
  RESULTS
  Either of two somatic gain-of-function mutations in the inward rectifier potassium channel KCNJ5 (Kir3.4) are present in approximately 40% of APAs. These tumor-causing mutations are heterozygous and alter the channel's selectivity filter. Mutant channels gain permeability to sodium, resulting in cellular depolarization and activation of voltage-gated calcium channels. The resulting calcium influx is sufficient to produce aldosterone secretion and cell proliferation, accounting for APA development. Germline KCNJ5 mutations also result in either of two autosomal-dominant syndromes featuring early-onset primary aldosteronism. Mutations identical or similar to those found in APAs result in massive bilateral adrenal hyperplasia. A different mutation at the same position produces a less severe syndrome without adrenal hyperplasia because this mutation results in Na-dependent cell lethality caused by a drastic increase in Na conductance.
  
  
  CONCLUSIONS
  These findings provide fundamental insight into the pathogenesis of APAs and primary aldosteronism, and have implications for new diagnostic and therapeutic strategies.
authors: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Ute I
authors: UI
authors: Scholl
authors: Richard P
authors: RP
authors: Lifton
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018246:Adrenocortical Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015640:Ion Channel Gating; D008297:Male; D009154:Mutation; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D012964:Sodium; D011188:Potassium; D002118:Calcium