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Nat Genet. 2013 Sep;45(9):1055-60. doi: 10.1038/ng.2716. Epub 2013 Aug 4.

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

Author information

1
Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

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.

PMID:
23913004
DOI:
10.1038/ng.2716
[Indexed for MEDLINE]

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