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

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 NeogiIan 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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

411 Citaten (Scopus)


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 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.

Originele taal-2Engels
Pagina's (van-tot)1055-1060
Aantal pagina's6
TijdschriftNature Genetics
Nummer van het tijdschrift9
StatusGepubliceerd - sep. 2013
Extern gepubliceerdJa


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