A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension.
BACKGROUND
Aldosterone production in the adrenal zona glomerulosa is mainly regulated by angiotensin II, [K(+)], and ACTH. Genetic deletion of subunits of K(+)-selective leak (KCNK) channels TWIK-related acid sensitive K(+)-1 and/or TWIK-related acid sensitive K(+)-3 in mice results in primary hyperaldosteronism, whereas mutations in the KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) gene are implicated in primary hyperaldosteronism and, in certain cases, in autonomous glomerulosa cell proliferation in humans.


OBJECTIVE
The objective of the study was to investigate the role of KCNK3, KCNK5, KCNK9, and KCNJ5 genes in a family with primary hyperaldosteronism and early-onset hypertension.


METHODS
Two patients, a mother and a daughter, presented with severe primary hyperaldosteronism, bilateral massive adrenal hyperplasia, and early-onset hypertension refractory to medical treatment. Genomic DNA was isolated and the exons of the entire coding regions of the above genes were amplified and sequenced. Electrophysiological studies were performed to determine the effect of identified mutation(s) on the membrane reversal potentials.


RESULTS
Sequencing of the KCNJ5 gene revealed a single, heterozygous guanine to thymine (G → T) substitution at nucleotide position 470 (n.G470T), resulting in isoleucine (I) to serine (S) substitution at amino acid 157 (p.I157S). This mutation results in loss of ion selectivity, cell membrane depolarization, increased Ca(2+) entry in adrenal glomerulosa cells, and increased aldosterone synthesis. Sequencing of the KCNK3, KCNK5, and KCNK9 genes revealed no mutations in our patients.


CONCLUSIONS
These findings explain the pathogenesis in a subset of patients with severe hypertension and implicate loss of K(+) channel selectivity in constitutive aldosterone production.
Division of Endocrinology, First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece. evangelia.charmandari@googlemail.com
Evangelia
E
Charmandari
Amalia
A
Sertedaki
Tomoshige
T
Kino
Christina
C
Merakou
Dax A
DA
Hoffman
Michael M
MM
Hatch
Darrell E
DE
Hurt
Lin
L
Lin
Paraskevi
P
Xekouki
Constantine A
CA
Stratakis
George P
GP
Chrousos
D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D006801:Humans; D006929:Hyperaldosteronism / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D017354:Point Mutation
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human