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

2013; Nature Portfolio; Volume: 45; Issue: 9 Linguagem: Inglês

10.1038/ng.2695

1546-1718

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 Benson, Tammy M. Brady, Jay R. Shapiro, Erin Loring, Carol Nelson‐Williams, Steven K. Libutti, Shrikant Mane, Per Hellman, Gunnar Westin, Göran Åkerström, Peyman Björklund, Tobias Carling, Christoph Fahlke, Patricia Hidalgo, Richard P. Lifton,

Ion Transport and Channel Regulation

Richard Lifton and colleagues identify somatic and germline mutations in the CACNA1D calcium channel gene in aldosterone-producing adenomas and primary aldosteronism. Their functional studies show that these mutations result in channel activation at more hyperpolarized membrane potentials, implicating increased Ca2+ influx in disease pathogenesis. 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.