Referenced in: Cav1.3

Automatically associated channels: Cav1.3 , Kir3.4

Title: Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension.

Authors: Elena A B Azizan, Hanne Poulsen, Petronel Tuluc, Junhua Zhou, Michael V Clausen, Andreas Lieb, Carmela Maniero, Sumedha Garg, Elena G Bochukova, Wanfeng Zhao, Lalarukh Haris Shaikh, Cheryl A Brighton, Ada E D Teo, Anthony P Davenport, Tanja Dekkers, Bas Tops, Benno Küsters, Jiri Ceral, Giles S H Yeo, Sudeshna Guha Neogi, Ian McFarlane, Nitzan Rosenfeld, Francesco Marass, James Hadfield, Wojciech Margas, Kanchan Chaggar, Miroslav Solar, Jaap Deinum, Annette C Dolphin, I Sadaf Farooqi, Joerg Striessnig, Poul Nissen, Morris J Brown

Journal, date & volume: Nat. Genet., 2013 Sep , 45, 1055-60

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23913004

Abstract
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.