Journal Article

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

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

2013

Overview

Morris Brown and colleagues identify somatic mutations in ATP1A1 and CACNA1D in aldosterone-producing adenomas with features resembling zonaglomerulosa cells. They further show that the ATP1A1 mutations cause inward leak currents under physiological conditions, whereas the CACNA1D mutations induce a shift of voltage-dependent gating to more negative potentials and suppress channel inactivation. 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 1 , 2 . 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 3 . 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 Ca v 1.3. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/514 / 631/337 / 692/308/2056 / 692/699/2743/1279 / Adrenal Cortex Diseases - complications / Adrenal Cortex Diseases - diagnosis / Adrenal Cortex Diseases - genetics / Adrenal glands / Agriculture / Amino Acid Substitution / Animal Genetics and Genomics / Biomedical research / Biomedicine / Calcium Channels, L-Type - chemistry / Calcium Channels, L-Type - genetics / Calcium Channels, L-Type - metabolism / Cancer Research / Cluster Analysis / Corticosteroids / Crystal structure / Design / Experiments / Female / G Protein-Coupled Inwardly-Rectifying Potassium Channels - genetics / G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism / Gene expression / Gene Expression Profiling / Gene Function / Gene mutations / Genetic aspects / Health aspects / Human Genetics / Humans / Hypertension / Hypertension - diagnosis / Hypertension - etiology / Hypertension - genetics / Inactivation / letter / Male / Mutation / Pathology / Protein Conformation / Risk factors / Rodents / Sodium-Potassium-Exchanging ATPase - chemistry / Sodium-Potassium-Exchanging ATPase - genetics / Sodium-Potassium-Exchanging ATPase - metabolism