Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension

Elena A B Azizan; Hanne Poulsen; Petronel Tuluc; Junhua Zhou; Michael Clausen; Andreas Lieb; Carmela Maniero; Sumedha Garg; Elena G Bochukova; Wanfeng Zhao; Lalarukh Haris Shaikh; Cheryl A Brighton; Ada E D Teo; Anthony P Davenport; Tanja Dekkers; Bas Tops; Benno Küsters; Jiri Ceral; Giles S H Yeo; Sudeshna Guha Neogi; Ian McFarlane; Nitzan Rosenfeld; Francesco Marass; James Hadfield; Wojciech Margas; Kanchan Chaggar; Miroslav Solar; Jaap Deinum; Annette C Dolphin; I Sadaf Farooqi; Joerg Striessnig; Poul Nissen; Morris J Brown

doi:10.1038/ng.2716

Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension

Elena A B Azizan, Hanne Poulsen, Petronel Tuluc, Junhua Zhou, Michael Clausen, Andreas Lieb, Carmela Maniero, Sumedha Garg, Elena G Bochukova, Wanfeng Zhao, Lalarukh Haris Shaikh, Cheryl A Brighton, Ada E D Teo, Anthony P Davenport, Tanja Dekkers, Bas Tops, Benno Küsters, Jiri Ceral, Giles S H Yeo, Sudeshna Guha NeogiIan McFarlane, Nitzan Rosenfeld, Francesco Marass, James Hadfield, Wojciech Margas, Kanchan Chaggar, Miroslav Solar, Jaap Deinum, Annette C Dolphin, I Sadaf Farooqi, Joerg Striessnig, Poul Nissen, Morris J Brown

Department of Molecular Biology and Genetics - Neurobiology

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs. We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa. We performed exome sequencing of ten zona glomerulosa-like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na(+)/K(+) ATPase α1 subunit, or CACNA1D, encoding Cav1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were

Original language	English
Journal	Nature Genetics
Volume	45
Issue	9
Pages (from-to)	1055-1060
Number of pages	6
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2716
Publication status	Published - 28 Aug 2013

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Azizan, E. A. B., Poulsen, H., Tuluc, P., Zhou, J., Clausen, M., Lieb, A., Maniero, C., Garg, S., Bochukova, E. G., Zhao, W., Shaikh, L. H., Brighton, C. A., Teo, A. E. D., Davenport, A. P., Dekkers, T., Tops, B., Küsters, B., Ceral, J., Yeo, G. S. H., ... Brown, M. J. (2013). Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nature Genetics, 45(9), 1055-1060. https://doi.org/10.1038/ng.2716

@article{e3c37ba789a744acbcf85b996344af90,

title = "Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension",

abstract = "At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs. We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa. We performed exome sequencing of ten zona glomerulosa-like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na(+)/K(+) ATPase α1 subunit, or CACNA1D, encoding Cav1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were ",

author = "Azizan, {Elena A B} and Hanne Poulsen and Petronel Tuluc and Junhua Zhou and Michael Clausen and Andreas Lieb and Carmela Maniero and Sumedha Garg and Bochukova, {Elena G} and Wanfeng Zhao and Shaikh, {Lalarukh Haris} and Brighton, {Cheryl A} and Teo, {Ada E D} and Davenport, {Anthony P} and Tanja Dekkers and Bas Tops and Benno K{\"u}sters and Jiri Ceral and Yeo, {Giles S H} and Neogi, {Sudeshna Guha} and Ian McFarlane and Nitzan Rosenfeld and Francesco Marass and James Hadfield and Wojciech Margas and Kanchan Chaggar and Miroslav Solar and Jaap Deinum and Dolphin, {Annette C} and Farooqi, {I Sadaf} and Joerg Striessnig and Poul Nissen and Brown, {Morris J}",

year = "2013",

month = aug,

day = "28",

doi = "10.1038/ng.2716",

language = "English",

volume = "45",

pages = "1055--1060",

journal = "Nature Genetics",

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Azizan, EAB, Poulsen, H, Tuluc, P, Zhou, J, Clausen, M, Lieb, A, Maniero, C, Garg, S, Bochukova, EG, Zhao, W, Shaikh, LH, Brighton, CA, Teo, AED, Davenport, AP, Dekkers, T, Tops, B, Küsters, B, Ceral, J, Yeo, GSH, Neogi, SG, McFarlane, I, Rosenfeld, N, Marass, F, Hadfield, J, Margas, W, Chaggar, K, Solar, M, Deinum, J, Dolphin, AC, Farooqi, IS, Striessnig, J, Nissen, P & Brown, MJ 2013, 'Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension', Nature Genetics, vol. 45, no. 9, pp. 1055-1060. https://doi.org/10.1038/ng.2716

TY - JOUR

T1 - Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension

AU - Azizan, Elena A B

AU - Poulsen, Hanne

AU - Tuluc, Petronel

AU - Zhou, Junhua

AU - Clausen, Michael

AU - Lieb, Andreas

AU - Maniero, Carmela

AU - Garg, Sumedha

AU - Bochukova, Elena G

AU - Zhao, Wanfeng

AU - Shaikh, Lalarukh Haris

AU - Brighton, Cheryl A

AU - Teo, Ada E D

AU - Davenport, Anthony P

AU - Dekkers, Tanja

AU - Tops, Bas

AU - Küsters, Benno

AU - Ceral, Jiri

AU - Yeo, Giles S H

AU - Neogi, Sudeshna Guha

AU - McFarlane, Ian

AU - Rosenfeld, Nitzan

AU - Marass, Francesco

AU - Hadfield, James

AU - Margas, Wojciech

AU - Chaggar, Kanchan

AU - Solar, Miroslav

AU - Deinum, Jaap

AU - Dolphin, Annette C

AU - Farooqi, I Sadaf

AU - Striessnig, Joerg

AU - Nissen, Poul

AU - Brown, Morris J

PY - 2013/8/28

Y1 - 2013/8/28

N2 - At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs. We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa. We performed exome sequencing of ten zona glomerulosa-like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na(+)/K(+) ATPase α1 subunit, or CACNA1D, encoding Cav1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were

AB - At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs. We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa. We performed exome sequencing of ten zona glomerulosa-like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na(+)/K(+) ATPase α1 subunit, or CACNA1D, encoding Cav1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were

U2 - 10.1038/ng.2716

DO - 10.1038/ng.2716

M3 - Journal article

C2 - 23913004

SN - 1061-4036

VL - 45

SP - 1055

EP - 1060

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension

Abstract

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