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

Ute I. Scholl, Gerald Goh, Gabriel Stölting, Regina Campos De Oliveira, Murim Choi, John D. Overton, Annabelle L. Fonseca, Reju Korah, Lee F. Starker, John W. Kunstman, Manju L. Prasad, Erum A. Hartung, Nelly Mauras, Matthew R. Benson, Tammy Brady, Jay R. Shapiro, Erin Loring, Carol Nelson-Williams, Steven K. Libutti, Shrikant ManePer Hellman, Gunnar Westin, Göran Åkerström, Peyman Björklund, Tobias Carling, Christoph Fahlke, Patricia Hidalgo, Richard P. Lifton

Research output: Contribution to journalArticle

268 Citations (Scopus)

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 Ca 2+ influx cause ∼40% of these tumors. 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 Ca 2+ influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. 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 Ca 2+ channel mutations in APAs and primary aldosteronism.

Original languageEnglish (US)
Pages (from-to)1050-1054
Number of pages5
JournalNature Genetics
Volume45
Issue number9
DOIs
StatePublished - Sep 2013

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Hyperaldosteronism
Calcium Channels
Aldosterone
Adenoma
Mutation
Zona Glomerulosa
S 6
Germ-Line Mutation
Potassium Channels
Salts
Cell Proliferation
Hormones
Hypertension
Genes
Neoplasms

ASJC Scopus subject areas

  • Genetics
  • Medicine(all)

Cite this

Scholl, U. I., Goh, G., Stölting, G., De Oliveira, R. C., Choi, M., Overton, J. D., ... Lifton, R. P. (2013). Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nature Genetics, 45(9), 1050-1054. https://doi.org/10.1038/ng.2695

Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. / Scholl, Ute I.; Goh, Gerald; Stölting, Gabriel; De Oliveira, Regina Campos; Choi, Murim; Overton, John D.; Fonseca, Annabelle L.; Korah, Reju; Starker, Lee F.; Kunstman, John W.; Prasad, Manju L.; Hartung, Erum A.; Mauras, Nelly; Benson, Matthew R.; Brady, Tammy; Shapiro, Jay R.; Loring, Erin; Nelson-Williams, Carol; Libutti, Steven K.; Mane, Shrikant; Hellman, Per; Westin, Gunnar; Åkerström, Göran; Björklund, Peyman; Carling, Tobias; Fahlke, Christoph; Hidalgo, Patricia; Lifton, Richard P.

In: Nature Genetics, Vol. 45, No. 9, 09.2013, p. 1050-1054.

Research output: Contribution to journalArticle

Scholl, UI, Goh, G, Stölting, G, De Oliveira, RC, Choi, M, Overton, JD, Fonseca, AL, Korah, R, Starker, LF, Kunstman, JW, Prasad, ML, Hartung, EA, Mauras, N, Benson, MR, Brady, T, Shapiro, JR, Loring, E, Nelson-Williams, C, Libutti, SK, Mane, S, Hellman, P, Westin, G, Åkerström, G, Björklund, P, Carling, T, Fahlke, C, Hidalgo, P & Lifton, RP 2013, 'Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism', Nature Genetics, vol. 45, no. 9, pp. 1050-1054. https://doi.org/10.1038/ng.2695
Scholl, Ute I. ; Goh, Gerald ; Stölting, Gabriel ; De Oliveira, Regina Campos ; Choi, Murim ; Overton, John D. ; Fonseca, Annabelle L. ; Korah, Reju ; Starker, Lee F. ; Kunstman, John W. ; Prasad, Manju L. ; Hartung, Erum A. ; Mauras, Nelly ; Benson, Matthew R. ; Brady, Tammy ; Shapiro, Jay R. ; Loring, Erin ; Nelson-Williams, Carol ; Libutti, Steven K. ; Mane, Shrikant ; Hellman, Per ; Westin, Gunnar ; Åkerström, Göran ; Björklund, Peyman ; Carling, Tobias ; Fahlke, Christoph ; Hidalgo, Patricia ; Lifton, Richard P. / Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. In: Nature Genetics. 2013 ; Vol. 45, No. 9. pp. 1050-1054.
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