A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension

Evangelia Charmandari, Amalia Sertedaki, Tomoshige Kino, Christina Merakou, Dax A. Hoffman, Michael M. Hatch, Darrell E. Hurt, Lin Lin, Paraskevi Xekouki, Constantine A. Stratakis, George P. Chrousos

Research output: Contribution to journalArticle

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Abstract

Context: 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. Patients and 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 Ca2+ 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.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Volume97
Issue number8
DOIs
Publication statusPublished - Aug 2012
Externally publishedYes

Fingerprint

Hyperaldosteronism
Point Mutation
Zona Glomerulosa
Genes
Hypertension
Aldosterone
Mutation
Substitution reactions
Inwardly Rectifying Potassium Channel
Acids
Thymine
Isoleucine
Depolarization
Cell proliferation
Guanine
Amino Acid Substitution
Cell membranes
Nuclear Family
Angiotensin II
Membrane Potentials

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension. / Charmandari, Evangelia; Sertedaki, Amalia; Kino, Tomoshige; Merakou, Christina; Hoffman, Dax A.; Hatch, Michael M.; Hurt, Darrell E.; Lin, Lin; Xekouki, Paraskevi; Stratakis, Constantine A.; Chrousos, George P.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 97, No. 8, 08.2012.

Research output: Contribution to journalArticle

Charmandari, E, Sertedaki, A, Kino, T, Merakou, C, Hoffman, DA, Hatch, MM, Hurt, DE, Lin, L, Xekouki, P, Stratakis, CA & Chrousos, GP 2012, 'A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension', Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 8. https://doi.org/10.1210/jc.2012-1334
Charmandari, Evangelia ; Sertedaki, Amalia ; Kino, Tomoshige ; Merakou, Christina ; Hoffman, Dax A. ; Hatch, Michael M. ; Hurt, Darrell E. ; Lin, Lin ; Xekouki, Paraskevi ; Stratakis, Constantine A. ; Chrousos, George P. / A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension. In: Journal of Clinical Endocrinology and Metabolism. 2012 ; Vol. 97, No. 8.
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abstract = "Context: 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. Patients and 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 Ca2+ 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.",
author = "Evangelia Charmandari and Amalia Sertedaki and Tomoshige Kino and Christina Merakou and Hoffman, {Dax A.} and Hatch, {Michael M.} and Hurt, {Darrell E.} and Lin Lin and Paraskevi Xekouki and Stratakis, {Constantine A.} and Chrousos, {George P.}",
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AU - Charmandari, Evangelia

AU - Sertedaki, Amalia

AU - Kino, Tomoshige

AU - Merakou, Christina

AU - Hoffman, Dax A.

AU - Hatch, Michael M.

AU - Hurt, Darrell E.

AU - Lin, Lin

AU - Xekouki, Paraskevi

AU - Stratakis, Constantine A.

AU - Chrousos, George P.

PY - 2012/8

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N2 - Context: 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. Patients and 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 Ca2+ 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.

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