KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism.
Primary aldosteronism is the most frequent cause of endocrine hypertension. Three forms of familial hyperaldosteronism (FH) have been described, named FH-I to -III. Recently, a mutation of KCNJ5 has been shown to be associated with FH-III, whereas the cause of FH-II is still unknown. In this study we searched for mutations in KCNJ5 in 46 patients from 21 families with FH, in which FH-I was excluded. We identified a new germline G151E mutation in 2 primary aldosteronism-affected subjects from an Italian family and 3 somatic mutations in aldosterone-producing adenomas, T158A described previously as a germline mutation associated with FH-III, and G151R and L168R both described as somatic mutations in aldosterone-producing adenoma. The phenotype of the family with the G151E mutation was remarkably milder compared with the previously described American family, in terms of both clinical and biochemical parameters. Furthermore, patients with somatic KCNJ5 mutations displayed a phenotype indistinguishable from that of sporadic primary aldosteronism. The functional characterization of the effects of the G151E mutation in vitro showed a profound alteration of the channel function, with loss of K(+) selectivity, Na(+) influx, and membrane depolarization. These alterations have been postulated to be responsible for voltage gate Ca(2+) channel activation, increase in cytosolic calcium, and stimulation of aldosterone production and adrenal cell proliferation. In conclusion, we describe herein a new mutation in the KCNJ5 potassium channel associated with FH-III, responsible for marked alterations of channel function but associated with a mild clinical and hormonal phenotype.
Division of Internal Medicine and Hypertension, University of Torino, Torino, Italy. paolo.mulatero@libero.it
Paolo
P
Mulatero
Philipp
P
Tauber
Maria-Christina
MC
Zennaro
Silvia
S
Monticone
Katharina
K
Lang
Felix
F
Beuschlein
Evelyn
E
Fischer
Davide
D
Tizzani
Anna
A
Pallauf
Andrea
A
Viola
Laurence
L
Amar
Tracy Ann
TA
Williams
Tim M
TM
Strom
Elisabeth
E
Graf
Sascha
S
Bandulik
David
D
Penton
Pierre-François
PF
Plouin
Richard
R
Warth
Bruno
B
Allolio
Xavier
X
Jeunemaitre
Franco
F
Veglio
Martin
M
Reincke
D000328:Adult; D005060:Europe; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D006929:Hyperaldosteronism / Q000145:classification / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017211:Treatment Failure; D044465:White People / Q000235:genetics
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D005938:Glucocorticoids; C484274:KCNJ5 protein, human