Journal Article

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

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

2013

Overview

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 Ca 2+ 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 Ca 2+ influx cause ∼40% of these tumors 1 . 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 2 . 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/1516 / Adrenal Cortex Neoplasms - genetics / Adrenal Cortex Neoplasms - metabolism / Adrenocortical Adenoma - genetics / Adrenocortical Adenoma - metabolism / Agriculture / Aldosterone - biosynthesis / Amino Acid Sequence / Animal Genetics and Genomics / Biomedicine / Calcium channels / Calcium Channels, L-Type - chemistry / Calcium Channels, L-Type - genetics / Calcium Channels, L-Type - metabolism / Cancer Research / Cell Line / Child / Child, Preschool / Deoxyribonucleic acid / DNA / Female / Gene Function / Gene mutations / Genetic aspects / Germ-Line Mutation / Health aspects / Human Genetics / Humans / Hyperaldosteronism / Hyperaldosteronism - genetics / Hyperaldosteronism - metabolism / Hypertension / Inactivation / letter / Male / Molecular Sequence Data / Mutation / Pedigree / Protein Conformation / Risk factors / Rodents / Sequence Alignment