Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells

Silvia Monticone, Namita G. Hattangady, Koshiro Nishimoto, Franco Mantero, Beatrice Rubin, Maria Verena Cicala, Raffaele Pezzani, Richard J. Auchus, Hans K. Ghayee, Hirotaka Shibata, Isao Kurihara, Tracy A. Williams, Judith G. Giri, Roni J. Bollag, Michael A. Edwards, Carlos M. Isales, William E. Rainey

Research output: Contribution to journalArticle

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Abstract

Context: Primary aldosteronism is a heterogeneous disease that includes both sporadic and familial forms. A point mutation in the KCNJ5 gene is responsible for familial hyperaldosteronism type III. Somatic mutations in KCNJ5 also occur in sporadic aldosterone producing adenomas (APA). Objective: The objective of the study was to define the effect of the KCNJ5 mutations on gene expression and aldosterone production using APA tissue and human adrenocortical cells. Methods: A microarray analysis was used to compare the transcriptome profiles of female-derived APA samples with and without KCNJ5 mutations and HAC15 adrenal cells overexpressing either mutated or wild-type KCNJ5. Real-time PCR validated a set of differentially expressed genes. Immunohistochemical staining localized the KCNJ5 expression in normal adrenals and APA. Results: We report a 38% (18 of 47) prevalence of KCNJ5 mutations in APA. KCNJ5 immunostaining was highest in the zona glomerulosa of NA and heterogeneous in APA tissue, and KCNJ5 mRNA was 4-fold higher in APA compared with normal adrenals (P < 0.05). APA with and without KCNJ5 mutations displayed slightly different gene expression patterns, notably the aldosterone synthase gene (CYP11B2) was more highly expressed in APA with KCNJ5 mutations. Overexpression of KCNJ5 mutations in HAC15 increased aldosterone production and altered expression of 36 genes by greater than 2.5-fold (P < 0.05). Real-time PCR confirmed increases in CYP11B2 and its transcriptional regulator, NR4A2. Conclusions: KCNJ5 mutations are prevalent in APA, and our data suggest that these mutations increase expression of CYP11B2 and NR4A2, thus increasing aldosterone production.

Original languageEnglish (US)
Pages (from-to)E1567-E1572
JournalJournal of Clinical Endocrinology and Metabolism
Volume97
Issue number8
DOIs
StatePublished - Aug 1 2012

Fingerprint

Adrenocortical Adenoma
Aldosterone
Gene expression
Adenoma
Gene Expression
Mutation
Cytochrome P-450 CYP11B2
Genes
Real-Time Polymerase Chain Reaction
Tissue
Zona Glomerulosa
Hyperaldosteronism
Microarray Analysis
Microarrays
Transcriptome
Point Mutation

ASJC Scopus subject areas

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

Cite this

Monticone, S., Hattangady, N. G., Nishimoto, K., Mantero, F., Rubin, B., Cicala, M. V., ... Rainey, W. E. (2012). Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. Journal of Clinical Endocrinology and Metabolism, 97(8), E1567-E1572. https://doi.org/10.1210/jc.2011-3132

Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. / Monticone, Silvia; Hattangady, Namita G.; Nishimoto, Koshiro; Mantero, Franco; Rubin, Beatrice; Cicala, Maria Verena; Pezzani, Raffaele; Auchus, Richard J.; Ghayee, Hans K.; Shibata, Hirotaka; Kurihara, Isao; Williams, Tracy A.; Giri, Judith G.; Bollag, Roni J.; Edwards, Michael A.; Isales, Carlos M.; Rainey, William E.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 97, No. 8, 01.08.2012, p. E1567-E1572.

Research output: Contribution to journalArticle

Monticone, S, Hattangady, NG, Nishimoto, K, Mantero, F, Rubin, B, Cicala, MV, Pezzani, R, Auchus, RJ, Ghayee, HK, Shibata, H, Kurihara, I, Williams, TA, Giri, JG, Bollag, RJ, Edwards, MA, Isales, CM & Rainey, WE 2012, 'Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells', Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 8, pp. E1567-E1572. https://doi.org/10.1210/jc.2011-3132
Monticone, Silvia ; Hattangady, Namita G. ; Nishimoto, Koshiro ; Mantero, Franco ; Rubin, Beatrice ; Cicala, Maria Verena ; Pezzani, Raffaele ; Auchus, Richard J. ; Ghayee, Hans K. ; Shibata, Hirotaka ; Kurihara, Isao ; Williams, Tracy A. ; Giri, Judith G. ; Bollag, Roni J. ; Edwards, Michael A. ; Isales, Carlos M. ; Rainey, William E. / Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. In: Journal of Clinical Endocrinology and Metabolism. 2012 ; Vol. 97, No. 8. pp. E1567-E1572.
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abstract = "Context: Primary aldosteronism is a heterogeneous disease that includes both sporadic and familial forms. A point mutation in the KCNJ5 gene is responsible for familial hyperaldosteronism type III. Somatic mutations in KCNJ5 also occur in sporadic aldosterone producing adenomas (APA). Objective: The objective of the study was to define the effect of the KCNJ5 mutations on gene expression and aldosterone production using APA tissue and human adrenocortical cells. Methods: A microarray analysis was used to compare the transcriptome profiles of female-derived APA samples with and without KCNJ5 mutations and HAC15 adrenal cells overexpressing either mutated or wild-type KCNJ5. Real-time PCR validated a set of differentially expressed genes. Immunohistochemical staining localized the KCNJ5 expression in normal adrenals and APA. Results: We report a 38{\%} (18 of 47) prevalence of KCNJ5 mutations in APA. KCNJ5 immunostaining was highest in the zona glomerulosa of NA and heterogeneous in APA tissue, and KCNJ5 mRNA was 4-fold higher in APA compared with normal adrenals (P < 0.05). APA with and without KCNJ5 mutations displayed slightly different gene expression patterns, notably the aldosterone synthase gene (CYP11B2) was more highly expressed in APA with KCNJ5 mutations. Overexpression of KCNJ5 mutations in HAC15 increased aldosterone production and altered expression of 36 genes by greater than 2.5-fold (P < 0.05). Real-time PCR confirmed increases in CYP11B2 and its transcriptional regulator, NR4A2. Conclusions: KCNJ5 mutations are prevalent in APA, and our data suggest that these mutations increase expression of CYP11B2 and NR4A2, thus increasing aldosterone production.",
author = "Silvia Monticone and Hattangady, {Namita G.} and Koshiro Nishimoto and Franco Mantero and Beatrice Rubin and Cicala, {Maria Verena} and Raffaele Pezzani and Auchus, {Richard J.} and Ghayee, {Hans K.} and Hirotaka Shibata and Isao Kurihara and Williams, {Tracy A.} and Giri, {Judith G.} and Bollag, {Roni J.} and Edwards, {Michael A.} and Isales, {Carlos M.} and Rainey, {William E.}",
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T1 - Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells

AU - Monticone, Silvia

AU - Hattangady, Namita G.

AU - Nishimoto, Koshiro

AU - Mantero, Franco

AU - Rubin, Beatrice

AU - Cicala, Maria Verena

AU - Pezzani, Raffaele

AU - Auchus, Richard J.

AU - Ghayee, Hans K.

AU - Shibata, Hirotaka

AU - Kurihara, Isao

AU - Williams, Tracy A.

AU - Giri, Judith G.

AU - Bollag, Roni J.

AU - Edwards, Michael A.

AU - Isales, Carlos M.

AU - Rainey, William E.

PY - 2012/8/1

Y1 - 2012/8/1

N2 - Context: Primary aldosteronism is a heterogeneous disease that includes both sporadic and familial forms. A point mutation in the KCNJ5 gene is responsible for familial hyperaldosteronism type III. Somatic mutations in KCNJ5 also occur in sporadic aldosterone producing adenomas (APA). Objective: The objective of the study was to define the effect of the KCNJ5 mutations on gene expression and aldosterone production using APA tissue and human adrenocortical cells. Methods: A microarray analysis was used to compare the transcriptome profiles of female-derived APA samples with and without KCNJ5 mutations and HAC15 adrenal cells overexpressing either mutated or wild-type KCNJ5. Real-time PCR validated a set of differentially expressed genes. Immunohistochemical staining localized the KCNJ5 expression in normal adrenals and APA. Results: We report a 38% (18 of 47) prevalence of KCNJ5 mutations in APA. KCNJ5 immunostaining was highest in the zona glomerulosa of NA and heterogeneous in APA tissue, and KCNJ5 mRNA was 4-fold higher in APA compared with normal adrenals (P < 0.05). APA with and without KCNJ5 mutations displayed slightly different gene expression patterns, notably the aldosterone synthase gene (CYP11B2) was more highly expressed in APA with KCNJ5 mutations. Overexpression of KCNJ5 mutations in HAC15 increased aldosterone production and altered expression of 36 genes by greater than 2.5-fold (P < 0.05). Real-time PCR confirmed increases in CYP11B2 and its transcriptional regulator, NR4A2. Conclusions: KCNJ5 mutations are prevalent in APA, and our data suggest that these mutations increase expression of CYP11B2 and NR4A2, thus increasing aldosterone production.

AB - Context: Primary aldosteronism is a heterogeneous disease that includes both sporadic and familial forms. A point mutation in the KCNJ5 gene is responsible for familial hyperaldosteronism type III. Somatic mutations in KCNJ5 also occur in sporadic aldosterone producing adenomas (APA). Objective: The objective of the study was to define the effect of the KCNJ5 mutations on gene expression and aldosterone production using APA tissue and human adrenocortical cells. Methods: A microarray analysis was used to compare the transcriptome profiles of female-derived APA samples with and without KCNJ5 mutations and HAC15 adrenal cells overexpressing either mutated or wild-type KCNJ5. Real-time PCR validated a set of differentially expressed genes. Immunohistochemical staining localized the KCNJ5 expression in normal adrenals and APA. Results: We report a 38% (18 of 47) prevalence of KCNJ5 mutations in APA. KCNJ5 immunostaining was highest in the zona glomerulosa of NA and heterogeneous in APA tissue, and KCNJ5 mRNA was 4-fold higher in APA compared with normal adrenals (P < 0.05). APA with and without KCNJ5 mutations displayed slightly different gene expression patterns, notably the aldosterone synthase gene (CYP11B2) was more highly expressed in APA with KCNJ5 mutations. Overexpression of KCNJ5 mutations in HAC15 increased aldosterone production and altered expression of 36 genes by greater than 2.5-fold (P < 0.05). Real-time PCR confirmed increases in CYP11B2 and its transcriptional regulator, NR4A2. Conclusions: KCNJ5 mutations are prevalent in APA, and our data suggest that these mutations increase expression of CYP11B2 and NR4A2, thus increasing aldosterone production.

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