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.
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NCBI Reference Sequence
We thank the subjects and families whose participation made this study possible. We thank the staff of the Yale West Campus Genomics Center, the Yale Cellular and Molecular Physiology Microscopy and Imaging Core, the Endocrine Surgical Laboratory, Clinical Research Centre, Uppsala University Hospital and the Department of Surgery, Montefiore Medical Center and Albert Einstein College of Medicine for their invaluable contributions to this research. J. Matthes (Universität Köln) and F. Lehmann-Horn (Universität Ulm) kindly provided us with clones for the α2δ subunits. This work was supported by the US National Institutes of Health (NIH) Centers for Mendelian Genomics (5U54HG006504), the Fondation Leducq Transatlantic Network in Hypertension and the Deutsche Forschungsgemeinschaft and by the Swedish Cancer Society, the Swedish Research Council and the Lions Cancer Fund, Uppsala. G.G. is supported by the Agency for Science, Technology and Research, Singapore. T.C. is a Doris Duke-Damon Runyon Clinical Investigator. R.P.L. is an Investigator of the Howard Hughes Medical Institute.
Supplementary Figures 1–5, Supplementary Tables 1–6 and Supplementary Note
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medizinische genetik (2018)