Title | Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Scholl, UI, Goh, G, Stölting, G, de Oliveira, RCampos, 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, Akerström, G, Björklund, P, Carling, T, Fahlke, C, Hidalgo, P, Lifton, RP |
Journal | Nat Genet |
Volume | 45 |
Issue | 9 |
Pagination | 1050-4 |
Date Published | 2013 Sep |
ISSN | 1546-1718 |
Keywords | Adrenal Cortex Neoplasms, Adrenocortical Adenoma, Aldosterone, Amino Acid Sequence, Calcium Channels, L-Type, Cell Line, Child, Child, Preschool, Female, Germ-Line Mutation, Humans, Hyperaldosteronism, Male, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Sequence Alignment |
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. |
DOI | 10.1038/ng.2695 |
Alternate Journal | Nat. Genet. |
PubMed ID | 23913001 |
PubMed Central ID | PMC3876926 |
Grant List | P30 DK079310 / DK / NIDDK NIH HHS / United States U54 HG006504 / HG / NHGRI NIH HHS / United States 5U54HG006504 / HG / NHGRI NIH HHS / United States / / Howard Hughes Medical Institute / United States |