학술논문
Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension.
Document Type
Article
Author
Azizan, Elena A B; Poulsen, Hanne; Tuluc, Petronel; Zhou, Junhua; Clausen, Michael V; Lieb, Andreas; Maniero, Carmela; Garg, Sumedha; Bochukova, Elena G; Zhao, Wanfeng; Shaikh, Lalarukh Haris; Brighton, Cheryl A; Teo, Ada E D; Davenport, Anthony P; Dekkers, Tanja; Tops, Bas; Küsters, Benno; Ceral, Jiri; Yeo, Giles S H; Neogi, Sudeshna Guha
Source
Subject
*SOMATIC mutation
*HYPERTENSION genetics
*ALDOSTERONE
*GLOMERULOSCLEROSIS
*ADENOSINE triphosphatase
*GENETIC code
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Language
ISSN
1061-4036
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. [ABSTRACT FROM AUTHOR]