期刊
NATURE GENETICS
卷 45, 期 9, 页码 1050-U126出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2695
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资金
- US National Institutes of Health (NIH) Centers for Mendelian Genomics [5U54HG006504]
- Fondation Leducq Transatlantic Network in Hypertension
- Deutsche Forschungsgemeinschaft
- Swedish Cancer Society
- Swedish Research Council
- Lions Cancer Fund, Uppsala
- Agency for Science, Technology and Research, Singapore
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 similar to 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 Ca2+ 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 Ca2+ channel mutations in APAs and primary aldosteronism.
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