EAB Azizan, H Poulsen, P Tuluc, J Zhou, MV Clausen, A Lieb, C Maniero, S Garg, EG Bochukova, W Zhao, LH Shaikh, CA Brighton, AED Teo, AP Davenport, T Dekkers, B Tops, B Küsters, J Ceral, GSH Yeo, SG Neogi, I McFarlane, N Rosenfeld, F Marass, J Hadfield, W Margas, K Chaggar, M Solar, J Deinum, AC Dolphin, IS Farooqi, J Striessnig, P Nissen, MJ Brown
At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs. We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa. We performed exome sequencing of ten zona glomerulosa-like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na(+)/K(+) ATPase α1 subunit, or CACNA1D, encoding Cav1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were <1 cm in diameter and had been overlooked on conventional adrenal imaging. Recognition of the distinct genotype and phenotype for this subset of APAs could facilitate diagnosis.