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- W2018889764 abstract "Conn's syndrome, which accounts for at least 5% of hypertension cases, is caused by aldosterone-producing adenomas (APAs) of the adrenal gland that are highly prone to somatic mutations(1,2). From exome sequencing of ten APAs from the zona glomerulosa (ZG), we identified four with mutations in ATP1A1 encoding the α1-subunit of the Na+/K+-ATPase(3).Expression of the most frequent mutation in ZG APAs, L104R ATP1A1, in Xenopus oocytes not only abrogated active ion transport, but allowed a significant inward current at physiological levels of Na+ and K+. Na+ and H+ can both leak, while K+ at high concentrations acts as a non-conducting partial inhibitor. The three other ATP1A1 mutations found in APAs caused inward leaking currents under physiological conditions as well. Inward leaking is expected to depolarize ZG cells, causing opening of voltage-gated Ca2+ channels and increased aldosterone production in response to the rising cytoplasmic Ca2+ levels.The L104 is completely conserved in Na+,K+-ATPases as well as in the closely related Ca2+-ATPases SERCA and PMCA. The residue is situated one helical turn above a kink in the middle of transmembrane helix 1, and is only 4A from a key ion binding residue. Recently, it was discovered in SERCA that a 12A sliding of M1 relative to M4 creates an opening within the membrane towards the the ion-accepting sites in the E1 conformation(4).Small ZG APAs with somatic mutations may thus prove to constitute a novel group of curable hypertension, and we can structurally and functionally explain why the mutations causes APAs.1 Choi et al., Science, 2011.2 Beuschlein et al., Nature Genetics, 2013.3 Azizan, Poulsen et al., Nature Genetics, 2013.4 Winther, Bublitz et al., Nature, 2013." @default.
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- W2018889764 date "2014-01-01" @default.
- W2018889764 modified "2023-09-26" @default.
- W2018889764 title "Somatic Mutations in the Na,K-ATPase Can Cause Hypertension" @default.
- W2018889764 doi "https://doi.org/10.1016/j.bpj.2013.11.2407" @default.
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