Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production
Summary
Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. In usual, the gain-of-function somatic mutations of ion channels or transporters are shown. We found intramembranous Val380Asp or Gly379Asp mutants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy by independent whole exome sequencing of 40 and 81 APAs. In addition, more two APAs with each variant (total, n = 6) were found. Prof. Takaoka investigated the effect of the amino acid substitution on the transmembrane domain by molecular simulation analysis. The results of molecular simulation suggest that amino acid mutations widen the cell-to-cell gap (see Figure).
Indeed, CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. The mutations of CADM1 make reversible hypertension and showed a role for gap communication in suppressing aldosterone production. These results are expected to bring new perspectives to the elucidation of the pathogenesis of drug-refractory hypertension.
Prof. Takaoka and Prof. Morris (2019)
Original article information
Authors
Xilin Wu, Elena A. B. Azizan, Emily Goodchild, Sumedha Garg, Man Hagiyama, Claudia P. Cabrera, Fabio L. Fernandes-Rosa, Sheerazed Boulkroun, Jyn Ling Kuan, Zenia Tiang, Alessia David, Masanori Murakami, Charles A. Mein, Eva Wozniak, Wanfeng Zhao, Alison Marker, Folma Buss, Rebecca S. Saleeb, Jackie Salsbury, Yuta Tezuka, Fumitoshi Satoh, Kenji Oki, Aaron M. Udager, Debbie L. Cohen, Heather Wachtel, Peter J. King, William M. Drake, Mark Gurnell, Jiri Ceral, Ales Ryska, Muaatamarulain Mustangin, Yin Ping Wong, Geok Chin Tan, Miroslav Solar, Martin Reincke, William E. Rainey, Roger S. Foo, Yutaka Takaoka, Sandra A. Murray, Maria-Christina Zennaro, Felix Beuschlein, Akihiko Ito & Morris J. Brown
Title
Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production
Journal
Nature Genetics 2023,