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

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Title:	Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension
Author(s):	Azizan, E.A.; Poulsen, H.; Tuluc, P.; Zhou, J; Clausen, M.V.; Lieb, A.; Maniero, C.; Garg, S.; Bochukova, E.G.; Zhao, W.; Shaikh, L.H.; Brighton, C.A.; Teo, A.E.; Davenport, A.P.; Dekkers, T.; Tops, B.; Kusters, B. ; Ceral, J.; Yeo, G.S.; Neogi, S.G.; McFarlane, I.; Rosenfeld, N.; Marass, F.; Hadfield, J.; Margas, W.; Chaggar, K.; Solar, M.; Deinum, J. ; Dolphin, A.C.; Farooqi, I.S.; Striessnig, J.; Nissen, P.; Brown, M.J.
Publication year:	2013
Source:	Nature Genetics, vol. 45, iss. 9, (2013), pp. 1055-1060
ISSN:	1061-4036
DOI:	https://doi.org/10.1038/ng.2716
Publication type:	Article / Letter to editor
Please use this identifier to cite or link to this item : https://hdl.handle.net/2066/140582
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Subject:	NCEBP 14: Cardiovascular diseases ONCOL 3 - Translational research DCN MP - Plasticity and memory
Organization:	Radiology Pathology Internal Medicine
Journal title:	Nature Genetics
Volume:	vol. 45
Issue:	iss. 9
Page start:	p. 1055
Page end:	p. 1060
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 alpha1 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.