Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension
Open accessAbstract
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 <1 cm in diameter and had been overlooked on conventional adrenal imaging. Recognition of the distinct genotype and phenotype for this subset of APAs could facilitate diagnosis.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CACNA1D is highly expressed in the adrenal glands, and when mutated gives rise to cerebral palsy/motor disorders; it has been linked to auditory processing and is among the positively selected genes in some vocal learners.
“It is highly expressed in the adrenal glands [90], and, when mutated, gives rise to cerebral palsy/motor disorders [91]. It has been linked to auditory processing [92], and said to be among the positively selected genes in some vocal learners [93].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [90]
Somatic driver mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 have been discovered in aldosterone-producing adenoma tissue, altogether accounting for most cases.
“Similarly, somatic driver mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 have been discovered in APA tissue, altogether accounting for most cases (157, 158, 161–164).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [164]
Cites
A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients
Rossi, G. P., Bernini, G., Caliumi, C., Desideri, G., Fabris, B., Ferri, C., Ganzaroli, C., Giacchetti, G., Letizia, C., Maccario, M., et al. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.07.059 · Cited by 1,467 · see citing works
K + Channel Mutations in Adrenal Aldosterone-Producing Adenomas and Hereditary Hypertension
Choi, M., Scholl, U. I., Yue, P., Björklund, P., Zhao, B., Nelson-Williams, C. J., Ji, W., Cho, Y., Patel, A. P., Men, C. J., et al. (2011) · Science · doi:10.1126/science.1198785 · Cited by 999 · see citing works
Crystal structure of the sodium–potassium pump
Morth, J. P., Pedersen, B. P., Toustrup-Jensen, M. S., Sørensen, T. L.-M., Petersen, J., Andersen, J. P., Vilsen, B., & Nissen, P. (2007) · Nature · doi:10.1038/nature06419 · Cited by 954 · see citing works
Self-citationSevere arrhythmia disorder caused by cardiac L-type calcium channel mutations
Splawski, I., Timothy, K. W., Decher, N., Kumar, P., Sachse, F. B., Beggs, A. H., Sanguinetti, M. C., & Keating, M. T. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502506102 · Cited by 624 · see citing works
Beuschlein, F., Boulkroun, S., Osswald, A., Wieland, T., Nielsen, H. N., Lichtenauer, U. D., Penton, D., Schack, V. R., Amar, L., Fischer, E., et al. (2013) · Nature Genetics · doi:10.1038/ng.2550 · Cited by 577 · see citing works
α1D (Cav1.3) Subunits Can Form L-type Ca2+ Channels Activating at Negative Voltages
Koschak, A., Reimer, D., Huber, I. G., Grabner, M., Glossmann, H. H., Engel, J., & Striessnig, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101469200 · Cited by 454 · see citing works
Self-citationLoss of Cav1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness
Baig, S. M., Koschak, A., Lieb, A., Gebhart, M., Dafinger, C., Nürnberg, G., Ali, A., Ahmad, I., Sinnegger-Brauns, M. J., Brandt, N., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2694 · Cited by 318 · see citing works
Self-citationAdrenocortical zonation in humans under normal and pathological conditions
Nishimoto, K., Nakagawa, K., Li, D., Kosaka, T., Oya, M., Mikami, S., Shibata, H., Itoh, H., Mitani, F., Yamazaki, T., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2010 · Cited by 310 · see citing works
Prevalence, Clinical, and Molecular Correlates of <i>KCNJ5</i> Mutations in Primary Aldosteronism
Boulkroun, S., Beuschlein, F., Rossi, G.-P., Golib-Dzib, J.-F., Fischer, E., Amar, L., Mulatero, P., Samson-Couterie, B., Hahner, S., Quinkler, M., et al. (2012) · Hypertension · doi:10.1161/hypertensionaha.111.186478 · Cited by 278 · see citing works
Self-citationBurton, T. J., Mackenzie, I. S., Balan, K., Koo, B., Bird, N., Soloviev, D. V., Azizan, E. A. B., Aigbirhio, F., Gurnell, M., & Brown, M. J. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1537 · Cited by 226 · see citing works
Self-citationCrystal structures of the calcium pump and sarcolipin in the Mg2+-bound E1 state
Toyoshima, C., Iwasawa, S., Ogawa, H., et al. (2013) · Nature · doi:10.1038/nature11899 · Cited by 225 · see citing works
The sarcolipin-bound calcium pump stabilizes calcium sites exposed to the cytoplasm
Winther, A.-M. L., Bublitz, M., Karlsen, J. L., MØLLER, J. V., Hansen, J. B., Nissen, P., & Buch-Pedersen, M. J. (2013) · Nature · doi:10.1038/nature11900 · Cited by 208 · see citing works
Self-citationAzizan, E. A. B. A., Lam, B., Newhouse, S., Zhou, J., Kuc, R. E., Clarke, J., Happerfield, L. C., Marker, A. J., Hoffman, G. J., & Brown, M. J. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-2965 · Cited by 190 · see citing works
Self-citationC-terminal modulator controls Ca2+-dependent gating of Cav1.4 L-type Ca2+ channels
Singh, A., Hamedinger, D., Hoda, J., Gebhart, M., Koschak, A., Romanin, C., & Striessnig, J. (2006) · Nature Neuroscience · doi:10.1038/nn1751 · Cited by 152 · see citing works
Self-citationNeurological disease mutations compromise a C-terminal ion pathway in the Na+/K+-ATPase
Poulsen, H., Khandelia, H., Morth, J. P., et al. (2010) · Nature · doi:10.1038/nature09309 · Cited by 141 · see citing works
Self-citationHemara‐Wahanui, A., Berjukow, S., Hope, C., Dearden, P. K., Wu, S., Wilson-Wheeler, J. C., Sharp, D. M., Lundon-Treweek, P., Clover, G. M., Hoda, J., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501907102 · Cited by 132 · see citing works
Self-citationA comprehensive review of the clinical aspects of primary aldosteronism
Rossi, G. P. (2011) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.76 · Cited by 113 · see citing works
Homeostatic Responses in the Adrenal Cortex to the Absence of Aldosterone in Mice
Lee, G., Makhanova, N., Caron, K. M., Sequeira-Lόpez, M. L. S., Gómez, R. A., Smithies, O., & Kim, H. (2005) · Endocrinology · doi:10.1210/en.2004-1102 · Cited by 95 · see citing works
Hoda, J., Zaghetto, F., Koschak, A., & Striessnig, J. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3054-04.2005 · Cited by 86 · see citing works
Self-citationMazzocchi, G., Neri, G., Ruciński, M., Rebuffat, P., Spinazzi, R., Malendowicz, L. K., & Nussdorfer, G. G. (2004) · Peptides · doi:10.1016/j.peptides.2004.05.011 · Cited by 70 · see citing works
A third Na + -binding site in the sodium pump
Li, C., Capendeguy, O., Geering, K., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505980102 · Cited by 61 · see citing works
Differential regulation of apoptosis in the normal human adrenal gland
Wolkersdörfer, G. W., Ehrhart‐Bornstein, M., Brauer, S., Marx, C., Scherbaum, W. A., & Bornstein, S. R. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.11.8923871 · Cited by 46 · see citing works
Braley, L. M., Williams, G. H., & MENACHERY, A. I. (1978) · Endocrinology · doi:10.1210/endo-103-6-1997 · Cited by 45 · see citing works
Calcium-channel blockade can mask the diagnosis of Conn's syndrome
Brown, M. J., & Hopper, R. (1999) · Postgraduate Medical Journal · doi:10.1136/pgmj.75.882.235 · Cited by 44 · see citing works
Self-citationShigematsu, K., Nishida, N., Sakai, H., et al. (2009) · Endocrine Pathology · doi:10.1007/s12022-009-9060-8 · Cited by 27 · see citing works
Effect of Extracellular pH on Presteady-State and Steady-State Current Mediated bythe Na+/K+ Pump
Vasilyev, A., Khater, K., & Rakowski, R. F. (2004) · The Journal of Membrane Biology · doi:10.1007/s00232-004-0660-4 · Cited by 23 · see citing works
Inward‐directed current generated by the Na+,K+ pump in Na+‐ and K+‐free medium
Efthymiadis, A., Rettinger, J., & Schwarz, W. H. (1993) · Cell Biology International · doi:10.1006/cbir.1993.1043 · Cited by 23 · see citing works
Insights into the mechanism by which inhibition of Na,K-ATPase stimulates aldosterone production
Yingst, D. R., Davis, J. N., Krenz, S., & SCHIEBINGER, R. J. (1999) · Metabolism · doi:10.1016/s0026-0495(99)90133-6 · Cited by 19 · see citing works
Inhibition of Aldosterone Secretion by Ouabain in Dog Adrenal Cortical Tissue
Cushman, P. (1969) · Endocrinology · doi:10.1210/endo-84-4-808 · Cited by 18 · see citing works
Kau, M., Kan, S., Wang, J., & Wang, P. S. (2005) · Journal of Cellular Physiology · doi:10.1002/jcp.20415 · Cited by 17 · see citing works
The Genetics of Primary Aldosteronism
Funder, J. W. (2012) · Hypertension · doi:10.1161/hypertensionaha.111.187682 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Funder, J. W., Carey, R. M., Mantero, F., Murad, M. H., Reincke, M., Shibata, H., Stowasser, M., & Young, W. F. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-4061 · Cited by 2,925 · see citing works
Williams, B., MacDonald, T. M., Morant, S., Webb, D. J., Sever, P., McInnes, G., Ford, I., Cruickshank, J. K., Caulfield, M. J., Salsbury, J., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(15)00257-3 · Cited by 1,308 · see citing works
Self-citationHypertension: Renin–Angiotensin–Aldosterone System Alterations
te Riet, L., van Esch, J. H. M., Roks, A. J. M., van den Meiracker, A. H., & Danser, A. H. J. (2015) · Circulation Research · doi:10.1161/circresaha.116.303587 · Cited by 706 · see citing works
Williams, B., MacDonald, T. M., Morant, S. V., Webb, D. J., Sever, P., McInnes, G. T., Ford, I., Cruickshank, J. K., Caulfield, M. J., Padmanabhan, S., et al. (2018) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(18)30071-8 · Cited by 347 · see citing works
Self-citationPrehistoric genomes reveal the genetic foundation and cost of horse domestication
Schubert, M., Jónsson, H., Chang, D., Der Sarkissian, C., Ermini, L., Ginolhac, A., Albrechtsen, A., Dupanloup, I., Foucal, A., Petersen, B., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1416991111 · Cited by 324 · see citing works
Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma
Fernandes-Rosa, F. L., Williams, T. A., Riester, A., Steichen, O., Beuschlein, F., Boulkroun, S., Strom, T. M., Monticone, S., Amar, L., Meatchi, T., et al. (2014) · Hypertension · doi:10.1161/hypertensionaha.114.03419 · Cited by 310 · see citing works
Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism
Arlt, W., Lang, K., Sitch, A. J., Dietz, A. S., Rhayem, Y., Bancos, I., Feuchtinger, A., Chortis, V., Gilligan, L. C., Ludwig, P., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.93136 · Cited by 281 · see citing works
Self-citationCACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels
Pinggera, A., Lieb, A., Benedetti, B., Lampert, M., Monteleone, S., Liedl, K. R., Tuluc, P., & Striessnig, J. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.11.020 · Cited by 180 · see citing works
Self-citationSelf-domestication in Homo sapiens: Insights from comparative genomics
Theofanopoulou, C., Gastaldon, S., O’Rourke, T., Samuels, B. D., Messner, A., Martins, P. T., Delogu, F., Alamri, S., & Boeckx, C. (2017) · PLOS ONE · doi:10.1371/journal.pone.0185306 · Cited by 174 · see citing works
Clinical characteristics of somatic mutations in Chinese patients with aldosterone-producing adenoma
Zheng, F.-F., Zhu, L.-M., Nie, A.-F., Li, X.-Y., Lin, J.-R., Zhang, K., Chen, J., Zhou, W.-L., Shen, Z.-J., Zhu, Y.-C., et al. (2015) · Hypertension · doi:10.1161/hypertensionaha.114.03346 · Cited by 151 · see citing works
Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism
Storbeck, K.-H., Schiffer, L., Baranowski, E. S., Chortis, V., Prete, A., Barnard, L., Gilligan, L. C., Taylor, A. E., Idkowiak, J., Arlt, W., et al. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00262 · Cited by 141 · see citing works
Role of Ca2+/Calmodulin-Dependent Protein Kinase Kinase in Adrenal Aldosterone Production
Nanba, K., Chen, A., Nishimoto, K., & Rainey, W. E. (2015) · Endocrinology · doi:10.1210/en.2014-1782 · Cited by 27 · see citing works
Felizola, S. J. A., Katsu, K., Ise, K., Nakamura, Y., Arai, Y., Satoh, F., & Sasano, H. (2015) · Endocrine Pathology · doi:10.1007/s12022-015-9366-7 · Cited by 15 · see citing works
Kamilaris, C. D. C., & Stratakis, C. A. (2018) · HORMONES · doi:10.1007/s42000-018-0072-y · Cited by 7 · see citing works
- Authors
- Azizan, E. A. B., Poulsen, H., Tuluc, P., Zhou, J., Clausen, M. V., 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., Neogi, S. G., McFarlane, I., Rosenfeld, N., Marass, F., Hadfield, J., Margas, W., Chaggar, K., Solar, M., Deinum, J., Dolphin, A. C., Farooqi, I. S., Striessnig, J., Nissen, P., & Brown, M. J.
- Affiliations
- University of Cambridge (GB)
- Aarhus University (DK)
- Universität Innsbruck (AT)
- National Health Service (GB)
- Radboud University Medical Center (NL)
- Addenbrooke's Hospital (GB)
- University College London (GB)
- Corresponding author
- Poulsen, Hanne
- Brown, Morris J
- ORCID
- Azizan, Elena A B
- Poulsen, Hanne
- Tuluc, Petronel
- Clausen, Michael V
- Lieb, Andreas
- Maniero, Carmela
- Garg, Sumedha
- Bochukova, Elena G
- Brighton, Cheryl A
- Teo, Ada E D
- Davenport, Anthony P
- Küsters, Benno
- Yeo, Giles S H
- Rosenfeld, Nitzan
- Marass, Francesco
- Hadfield, James
- Margas, Wojciech
- Deinum, Jaap
- Dolphin, Annette C
- Farooqi, I Sadaf
- Nissen, Poul
- Brown, Morris J
- Venue
- Nature Genetics
- Published
- 2013-08-04
- Volume
- 45
- Issue
- 9
- Pages
- 1055-1060
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2061341378
- Cited by
- 544
- References
- 31
- Citations by year
- 2026: 32 · 2025: 34 · 2024: 23 · 2023: 36 · 2022: 42 · 2021: 48 · 2020: 38 · 2019: 48 · 2018: 39 · 2017: 48 · 2016: 48 · 2015: 58 · 2014: 38 · 2013: 7 · 2012: 1
- FWCI
- 39.67
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (098360/Z/12/Z, 085686/Z/08/A, 098360, 098497)
- Cancer Research UK (11906, 22310)
- British Heart Foundation (PG/07/085/23349, FS/11/35/28871)
- Medical Research Council (MR/K501050/1)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- somatic mutations, ATP1A1, CACNA1D, aldosterone-producing adenoma, adrenal hypertension, zona glomerulosa, Na+/K+-ATPase, Cav1.3, L-type calcium channels, gain-of-function mutations, KCNJ5, voltage-dependent gating, channel inactivation, genotype-phenotype correlation, adrenal imaging
- MeSH terms
- Sodium-Potassium-Exchanging ATPase, Adrenal Cortex Diseases, Female, Humans, Hypertension, Male, Mutation, Protein Conformation, Cluster Analysis, Amino Acid Substitution, Calcium Channels, L-Type, Gene Expression Profiling, G Protein-Coupled Inwardly-Rectifying Potassium Channels
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
