Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter

Tobias Åkerström, Joakim Crona, Alberto Delgado Verdugo, Lee F. Starker, Kenko Cupisti, Holger S. Willenberg, Wolfram T. Knoefel, Wolfgang Saeger, Alfred Feller, Julian Ip, Patsy Soon, Martin Anlauf, Pier F. Alesina, Kurt W. Schmid, Myriam Decaussin, Pierre Levillain, Bo Wängberg, Jean Louis Peix, Bruce Robinson, Jan ZedeniusMartin Bäckdahl, Stefano Caramuta, K. Alexander Iwen, Johan Botling, Peter Stålberg, Jean Louis Kraimps, Henning Dralle, Per Hellman, Stan Sidhu, Gunnar Westin, Hendrik Lehnert, Martin K. Walz, Göran Åkerström, Tobias Carling, Murim Choi, Richard P. Lifton, Peyman Björklund

Research output: Contribution to journalArticle

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Abstract

Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined. Materials and Methods: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers. Results: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005). Discussion: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

Original languageEnglish
Article numbere41926
JournalPLoS ONE
Volume7
Issue number7
DOIs
StatePublished - 27 Jul 2012

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somatic mutation
aldosterone
Potassium Channels
potassium channels
Aldosterone
mutation
Mutation
adenoma
Adenoma
Hyperaldosteronism
Cell proliferation
hyperplasia
cell proliferation
Hyperplasia
missense mutation
Depolarization
Cell Proliferation
carcinogenesis
hypertension
Missense Mutation

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Åkerström, T., Crona, J., Delgado Verdugo, A., Starker, L. F., Cupisti, K., Willenberg, H. S., ... Björklund, P. (2012). Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PLoS ONE, 7(7), [e41926]. https://doi.org/10.1371/journal.pone.0041926
Åkerström, Tobias ; Crona, Joakim ; Delgado Verdugo, Alberto ; Starker, Lee F. ; Cupisti, Kenko ; Willenberg, Holger S. ; Knoefel, Wolfram T. ; Saeger, Wolfgang ; Feller, Alfred ; Ip, Julian ; Soon, Patsy ; Anlauf, Martin ; Alesina, Pier F. ; Schmid, Kurt W. ; Decaussin, Myriam ; Levillain, Pierre ; Wängberg, Bo ; Peix, Jean Louis ; Robinson, Bruce ; Zedenius, Jan ; Bäckdahl, Martin ; Caramuta, Stefano ; Iwen, K. Alexander ; Botling, Johan ; Stålberg, Peter ; Kraimps, Jean Louis ; Dralle, Henning ; Hellman, Per ; Sidhu, Stan ; Westin, Gunnar ; Lehnert, Hendrik ; Walz, Martin K. ; Åkerström, Göran ; Carling, Tobias ; Choi, Murim ; Lifton, Richard P. ; Björklund, Peyman. / Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. In: PLoS ONE. 2012 ; Vol. 7, No. 7.
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title = "Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter",
abstract = "Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined. Materials and Methods: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers. Results: G151R or L168R somatic mutations were identified in 47{\%} of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40{\%} of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24{\%}). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005). Discussion: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.",
author = "Tobias {\AA}kerstr{\"o}m and Joakim Crona and {Delgado Verdugo}, Alberto and Starker, {Lee F.} and Kenko Cupisti and Willenberg, {Holger S.} and Knoefel, {Wolfram T.} and Wolfgang Saeger and Alfred Feller and Julian Ip and Patsy Soon and Martin Anlauf and Alesina, {Pier F.} and Schmid, {Kurt W.} and Myriam Decaussin and Pierre Levillain and Bo W{\"a}ngberg and Peix, {Jean Louis} and Bruce Robinson and Jan Zedenius and Martin B{\"a}ckdahl and Stefano Caramuta and Iwen, {K. Alexander} and Johan Botling and Peter St{\aa}lberg and Kraimps, {Jean Louis} and Henning Dralle and Per Hellman and Stan Sidhu and Gunnar Westin and Hendrik Lehnert and Walz, {Martin K.} and G{\"o}ran {\AA}kerstr{\"o}m and Tobias Carling and Murim Choi and Lifton, {Richard P.} and Peyman Bj{\"o}rklund",
year = "2012",
month = "7",
day = "27",
doi = "10.1371/journal.pone.0041926",
language = "English",
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Åkerström, T, Crona, J, Delgado Verdugo, A, Starker, LF, Cupisti, K, Willenberg, HS, Knoefel, WT, Saeger, W, Feller, A, Ip, J, Soon, P, Anlauf, M, Alesina, PF, Schmid, KW, Decaussin, M, Levillain, P, Wängberg, B, Peix, JL, Robinson, B, Zedenius, J, Bäckdahl, M, Caramuta, S, Iwen, KA, Botling, J, Stålberg, P, Kraimps, JL, Dralle, H, Hellman, P, Sidhu, S, Westin, G, Lehnert, H, Walz, MK, Åkerström, G, Carling, T, Choi, M, Lifton, RP & Björklund, P 2012, 'Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter', PLoS ONE, vol. 7, no. 7, e41926. https://doi.org/10.1371/journal.pone.0041926

Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. / Åkerström, Tobias; Crona, Joakim; Delgado Verdugo, Alberto; Starker, Lee F.; Cupisti, Kenko; Willenberg, Holger S.; Knoefel, Wolfram T.; Saeger, Wolfgang; Feller, Alfred; Ip, Julian; Soon, Patsy; Anlauf, Martin; Alesina, Pier F.; Schmid, Kurt W.; Decaussin, Myriam; Levillain, Pierre; Wängberg, Bo; Peix, Jean Louis; Robinson, Bruce; Zedenius, Jan; Bäckdahl, Martin; Caramuta, Stefano; Iwen, K. Alexander; Botling, Johan; Stålberg, Peter; Kraimps, Jean Louis; Dralle, Henning; Hellman, Per; Sidhu, Stan; Westin, Gunnar; Lehnert, Hendrik; Walz, Martin K.; Åkerström, Göran; Carling, Tobias; Choi, Murim; Lifton, Richard P.; Björklund, Peyman.

In: PLoS ONE, Vol. 7, No. 7, e41926, 27.07.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter

AU - Åkerström, Tobias

AU - Crona, Joakim

AU - Delgado Verdugo, Alberto

AU - Starker, Lee F.

AU - Cupisti, Kenko

AU - Willenberg, Holger S.

AU - Knoefel, Wolfram T.

AU - Saeger, Wolfgang

AU - Feller, Alfred

AU - Ip, Julian

AU - Soon, Patsy

AU - Anlauf, Martin

AU - Alesina, Pier F.

AU - Schmid, Kurt W.

AU - Decaussin, Myriam

AU - Levillain, Pierre

AU - Wängberg, Bo

AU - Peix, Jean Louis

AU - Robinson, Bruce

AU - Zedenius, Jan

AU - Bäckdahl, Martin

AU - Caramuta, Stefano

AU - Iwen, K. Alexander

AU - Botling, Johan

AU - Stålberg, Peter

AU - Kraimps, Jean Louis

AU - Dralle, Henning

AU - Hellman, Per

AU - Sidhu, Stan

AU - Westin, Gunnar

AU - Lehnert, Hendrik

AU - Walz, Martin K.

AU - Åkerström, Göran

AU - Carling, Tobias

AU - Choi, Murim

AU - Lifton, Richard P.

AU - Björklund, Peyman

PY - 2012/7/27

Y1 - 2012/7/27

N2 - Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined. Materials and Methods: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers. Results: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005). Discussion: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

AB - Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined. Materials and Methods: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers. Results: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005). Discussion: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

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DO - 10.1371/journal.pone.0041926

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