KCNJ5 mutations in the National Institutes of Health cohort of patients with primary hyperaldosteronism: an infrequent genetic cause of Conn's syndrome.
KCNJ5 mutations were recently described in primary hyperaldosteronism (PH or Conn's syndrome). The frequency of these mutations in PH and the way KCNJ5 defects cause disease remain unknown. A total of 53 patients with PH have been seen at the National Institutes of Health over the last 12 years. Their peripheral and tumor DNAs (the latter from 16 that were operated) were screened for KCNJ5 mutations; functional studies on the identified defects were performed after transient transfection. Only two mutations were identified, and both in the tumor DNA only. There were no germline sequencing defects in any of the patients except for known synonymous variants of the KCNJ5 gene. One mutation was the previously described c.G451C alteration; the other was a novel one in the same codon: c.G451A; both lead to the same amino acid substitution (G151R) in the KCNJ5 protein. Functional studies confirmed previous findings that both mutations caused loss of channel selectivity and a positive shift in the reversal potential. In conclusion, the KCNJ5 protein was strongly expressed in the zona glomerulosa of normal adrenal glands but showed variable expression in the aldosterone-producing adenomas with and without mutation. The rate of KCNJ5 mutations among patients with PH and/or their tumors is substantially lower than what was previously reported. The G151R amino acid substitution appears to be the most frequent one so far detected in PH, despite additional nucleotide changes. The mutation causes loss of this potassium channel's selectivity and may assist in the design of new therapies for PH.
Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, NIH, Bethesda, Maryland 20892, USA.
Paraskevi
P
Xekouki
Michael M
MM
Hatch
Lin
L
Lin
De Alexandre
de A
Rodrigo
Monalisa
M
Azevedo
Maria
M
de la Luz Sierra
Isaac
I
Levy
Emmanouil
E
Saloustros
Andreas
A
Moraitis
Anelia
A
Horvath
E
E
Kebebew
Dax A
DA
Hoffman
Constantine A
CA
Stratakis
D000236:Adenoma / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D009316:National Institutes of Health (U.S.); D014481:United States
D004273:DNA, Neoplasm; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human