title: a Novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III.
abstract: BACKGROUND
  Primary aldosteronism is a heterogeneous group of disorders comprising both sporadic and familial forms. Mutations in the KCNJ5 gene, which encodes the inward rectifier K(+) channel 4 (G protein-activated inward rectifier K(+) channel 4, Kir3.4), cause familial hyperaldosteronism type III (FH-III) and are involved in the pathogenesis of sporadic aldosterone-producing adenomas.
  
  
  OBJECTIVE
  The objective of the study was to characterize the effects of a newly described KCNJ5 mutation in vitro.
  
  
  METHODS
  The index case is a 62-year-old woman affected by primary aldosteronism, who underwent left adrenalectomy after workup for adrenal adenoma. Exon 1 of KCNJ5 was PCR amplified from adrenal tissue and peripheral blood and sequenced. Electrophysiological and gene expression studies were performed to establish the functional effects of the new mutation on the membrane potential and adrenal cell CYP11B2 expression.
  
  
  RESULTS
  KCNJ5 sequencing in the index case revealed a new p.Y152C germline mutation; interestingly, the phenotype of the patient was milder than most of the previously described FH-III families. The tyrosine-to-cysteine substitution resulted in pathological Na(+) permeability, cell membrane depolarization, and disturbed intracellular Ca(2+) homeostasis, effects similar, albeit smaller, to the ones demonstrated for other KCNJ5 mutations. Gene expression studies revealed an increased expression of CYP11B2 and its transcriptional regulator NR4A2 in HAC15 adrenal cells overexpressing KCNJ5(Y152C) compared to the wild-type channel. The effect was clearly Ca(2+)-dependent, because it was abolished by the calcium channel blocker nifedipine.
  
  
  CONCLUSIONS
  Herein we describe a new germline mutation in KCNJ5 responsible for FH-III.
authors.affiliation: Department of Medical Sciences, Medicina Interna 4, University of Torino, Via Genova 3, 10126 Torino, Italy. monticone.silvia@libero.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Monticone
authors.forename: Namita G
authors.initials: NG
authors.lastname: Hattangady
authors.forename: David
authors.initials: D
authors.lastname: Penton
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Isales
authors.forename: Michael A
authors.initials: MA
authors.lastname: Edwards
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Williams
authors.forename: Christina
authors.initials: C
authors.lastname: Sterner
authors.forename: Richard
authors.initials: R
authors.lastname: Warth
authors.forename: Paolo
authors.initials: P
authors.lastname: Mulatero
authors.forename: William E
authors.initials: WE
authors.lastname: Rainey
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000315:Adrenalectomy; D002118:Calcium / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D005192:Family Health; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics / Q000473:pathology / Q000601:surgery; D008875:Middle Aged; D017354:Point Mutation
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D019405:Cytochrome P-450 CYP11B2; D002118:Calcium
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