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Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism

Nature Genetics volume 45, pages 1050–1054 (2013)Cite this article

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Abstract

Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca2+ influx cause ∼40% of these tumors1. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca2+ influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa2. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca2+ channel mutations in APAs and primary aldosteronism.

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Figure 1: CACNA1D mutations in APAs and primary aldosteronism.
Figure 2: Transmembrane structure of Cav1.3.
Figure 3: Immunohistochemistry of Cav1.3 in human adrenal gland.
Figure 4: Cav1.3 alterations shift the voltage dependence of activation to more hyperpolarized potentials.

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NCBI Reference Sequence

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Acknowledgements

We thank the subjects and families whose participation made this study possible. We thank the staff of the Yale West Campus Genomics Center, the Yale Cellular and Molecular Physiology Microscopy and Imaging Core, the Endocrine Surgical Laboratory, Clinical Research Centre, Uppsala University Hospital and the Department of Surgery, Montefiore Medical Center and Albert Einstein College of Medicine for their invaluable contributions to this research. J. Matthes (Universität Köln) and F. Lehmann-Horn (Universität Ulm) kindly provided us with clones for the α2δ subunits. This work was supported by the US National Institutes of Health (NIH) Centers for Mendelian Genomics (5U54HG006504), the Fondation Leducq Transatlantic Network in Hypertension and the Deutsche Forschungsgemeinschaft and by the Swedish Cancer Society, the Swedish Research Council and the Lions Cancer Fund, Uppsala. G.G. is supported by the Agency for Science, Technology and Research, Singapore. T.C. is a Doris Duke-Damon Runyon Clinical Investigator. R.P.L. is an Investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Ute I Scholl, Gerald Goh and Gabriel Stölting: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA

    Ute I Scholl, Gerald Goh, Murim Choi, John D Overton, Erin Loring, Carol Nelson-Williams, Shrikant Mane & Richard P Lifton

  2. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA

    Ute I Scholl, Gerald Goh, Murim Choi, Erin Loring, Carol Nelson-Williams & Richard P Lifton

  3. Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich, Jülich, Germany

    Gabriel Stölting, Christoph Fahlke & Patricia Hidalgo

  4. Institut für Neurophysiologie, Medizinische Hochschule Hannover, Hannover, Germany

    Regina Campos de Oliveira

  5. Yale Center for Mendelian Genomics, New Haven, Connecticut, USA

    Murim Choi, John D Overton, Erin Loring, Shrikant Mane & Richard P Lifton

  6. Department of Surgery, Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, Connecticut, USA

    Annabelle L Fonseca, Reju Korah, Lee F Starker, John W Kunstman & Tobias Carling

  7. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

    Lee F Starker, Per Hellman, Gunnar Westin, Göran Åkerström & Peyman Björklund

  8. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA

    Manju L Prasad

  9. Division of General Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Erum A Hartung

  10. Nemours Children's Clinic, Jacksonville, Florida, USA

    Nelly Mauras & Matthew R Benson

  11. Johns Hopkins Pediatric Nephrology, Baltimore, Maryland, USA

    Tammy Brady

  12. Osteogenesis Imperfecta Program, Kennedy Krieger Institute, Baltimore, Maryland, USA

    Jay R Shapiro

  13. Department of Surgery, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, USA

    Steven K Libutti

  14. Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA

    Tobias Carling

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  1. Ute I Scholl
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Contributions

A.L.F., L.F.S., J.W.K., M.L.P., E.A.H., N.M., M.R.B., T.B., J.R.S., E.L., U.I.S., R.P.L., S.K.L., P. Hellman, G.W., G.Å., P.B. and T.C. ascertained and recruited subjects and obtained samples and medical records. A.L.F., R.K., L.F.S., U.I.S., P.B. and C.N.-W. prepared DNA and RNA samples and maintained sample archives. J.D.O. and S.M. performed exome sequencing. U.I.S. and G.G. performed and analyzed targeted DNA and RNA sequencing. G.G., M.C. and R.P.L. analyzed exome sequencing results. U.I.S. and R.K. performed immunohistochemistry. U.I.S., G.S., R.C.d.O., C.F. and P. Hidalgo made constructs and performed and analyzed electrophysiology. U.I.S., G.G., G.S., C.F., P. Hidalgo and R.P.L. wrote the manuscript.

Corresponding author

Correspondence to Richard P Lifton.

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Supplementary Figures 1–5, Supplementary Tables 1–6 and Supplementary Note (PDF 532 kb)

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Scholl, U., Goh, G., Stölting, G. et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 45, 1050–1054 (2013). https://doi.org/10.1038/ng.2695

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