1. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension.
- Author
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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, and Neogi, Sudeshna Guha
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SOMATIC mutation , *HYPERTENSION genetics , *ALDOSTERONE , *GLOMERULOSCLEROSIS , *ADENOSINE triphosphatase , *GENETIC code - 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]
- Published
- 2013
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