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



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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  1. 1

    Choi, M. et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331, 768–772 (2011).

    CAS  Article  Google Scholar 

  2. 2

    Spät, A. & Hunyady, L. Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol. Rev. 84, 489–539 (2004).

    Article  Google Scholar 

  3. 3

    Rossi, G.P. et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J. Am. Coll. Cardiol. 48, 2293–2300 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Conn, J.W. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J. Lab. Clin. Med. 45, 3–17 (1955).

    CAS  PubMed  Google Scholar 

  5. 5

    Scholl, U.I. et al. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc. Natl. Acad. Sci. USA 109, 2533–2538 (2012).

    CAS  Article  Google Scholar 

  6. 6

    Tadjine, M., Lampron, A., Ouadi, L. & Bourdeau, I. Frequent mutations of β-catenin gene in sporadic secreting adrenocortical adenomas. Clin. Endocrinol. 68, 264–270 (2008).

    CAS  Google Scholar 

  7. 7

    Catterall, W.A. Signaling complexes of voltage-gated sodium and calcium channels. Neurosci. Lett. 486, 107–116 (2010).

    CAS  Article  Google Scholar 

  8. 8

    Baig, S.M. et al. Loss of Cav1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nat. Neurosci. 14, 77–84 (2011).

    CAS  Article  Google Scholar 

  9. 9

    Hu, C., Rusin, C.G., Tan, Z., Guagliardo, N.A. & Barrett, P.Q. Zona glomerulosa cells of the mouse adrenal cortex are intrinsic electrical oscillators. J. Clin. Invest. 122, 2046–2053 (2012).

    CAS  Article  Google Scholar 

  10. 10

    Tadross, M.R., Ben Johny, M. & Yue, D.T. Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Cav1.3 channels. J. Gen. Physiol. 135, 197–215 (2010).

    CAS  Article  Google Scholar 

  11. 11

    Clark, V.E. et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1 and SMO. Science 339, 1077–1080 (2013).

    CAS  Article  Google Scholar 

  12. 12

    Platzer, J. et al. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell 102, 89–97 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Hering, S. et al. Pore stability and gating in voltage-activated calcium channels. Channels 2, 61–69 (2008).

    Article  Google Scholar 

  14. 14

    Hoda, J.C., Zaghetto, F., Koschak, A. & Striessnig, J. Congenital stationary night blindness type 2 mutations S229P, G369D, L1068P, and W1440X alter channel gating or functional expression of Cav1.4 L-type Ca2+ channels. J. Neurosci. 25, 252–259 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Hemara-Wahanui, A. et al. A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation. Proc. Natl. Acad. Sci. USA 102, 7553–7558 (2005).

    CAS  Article  Google Scholar 

  16. 16

    Splawski, I. et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc. Natl. Acad. Sci. USA 102, 8089–8096 (2005).

    CAS  Article  Google Scholar 

  17. 17

    Hans, M. et al. Functional consequences of mutations in the human α1A calcium channel subunit linked to familial hemiplegic migraine. J. Neurosci. 19, 1610–1619 (1999).

    CAS  Article  Google Scholar 

  18. 18

    Battistini, S. et al. A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia. Neurology 53, 38–43 (1999).

    CAS  Article  Google Scholar 

  19. 19

    Scholl, U.I. & Lifton, R.P. New insights into aldosterone-producing adenomas and hereditary aldosteronism: mutations in the K+ channel KCNJ5. Curr. Opin. Nephrol. Hypertens. 22, 141–147 (2013).

    CAS  Article  Google Scholar 

  20. 20

    Beuschlein, F. et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat. Genet. 45, 440–444 (2013).

    CAS  Article  Google Scholar 

  21. 21

    Kang, S. et al. Cav1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease. Nat. Commun. 3, 1146 (2012).

    Article  Google Scholar 

  22. 22

    Peloquin, J.B., Rehak, R., Doering, C.J. & McRory, J.E. Functional analysis of congenital stationary night blindness type-2 CACNA1F mutations F742C, G1007R, and R1049W. Neuroscience 150, 335–345 (2007).

    CAS  Article  Google Scholar 

  23. 23

    Ducros, A. et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N. Engl. J. Med. 345, 17–24 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Brenner, C.H. A note on paternity computation in cases lacking a mother. Transfusion 33, 51–54 (1993).

    CAS  Article  Google Scholar 

  25. 25

    Butler, J.M., Schoske, R., Vallone, P.M., Redman, J.W. & Kline, M.C. Allele frequencies for 15 autosomal STR loci on U.S. Caucasian, African American, and Hispanic populations. J. Forensic Sci. 48, 908–911 (2003).

    PubMed  Google Scholar 

  26. 26

    Gonzalez-Gutierrez, G. et al. The guanylate kinase domain of the β-subunit of voltage-gated calcium channels suffices to modulate gating. Proc. Natl. Acad. Sci. USA 105, 14198–14203 (2008).

    CAS  Article  Google Scholar 

  27. 27

    Marcantoni, A. et al. Loss of Cav1.3 channels reveals the critical role of L-type and BK channel coupling in pacemaking mouse adrenal chromaffin cells. J. Neurosci. 30, 491–504 (2010).

    CAS  Article  Google Scholar 

  28. 28

    Roberts-Crowley, M.L. & Rittenhouse, A.R. Arachidonic acid inhibition of L-type calcium (Cav1.3b) channels varies with accessory Cavβ subunits. J. Gen. Physiol. 133, 387–403 (2009).

    CAS  Article  Google Scholar 

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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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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.

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Correspondence to Richard P Lifton.

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The authors declare no competing financial interests.

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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).

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