期刊
NATURE GENETICS
卷 45, 期 9, 页码 1055-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2716
关键词
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资金
- NIHR Cambridge BRC
- British Heart Foundation [PG/07/085/23349]
- Wellcome Trust [085686/Z/08/A, 098360/Z/12/Z]
- NIHR Cambridge Biomedical Research Centre (Cardiovascular)
- NIHR Senior Investigator award
- Austin Doyle Award
- Servier Australia
- Wellcome Trust PhD program in Metabolic and Cardiovascular Disease
- Cambridge Overseas Trust
- Sun Hung Kai Properties-Kwoks' Foundation PhD program
- European Union [FP7-HEALTH-2009-241592 EurOCHIP, FP7-FOOD-266408 Full4Health]
- The Carlsberg Foundation
- The Lundbeck Foundation
- L'Oreal/UNESCO
- Austrian Science Fund [F44020]
- University College London, UK
- program PRVOUK [P037/03]
- MRC [G0600717, MC_UU_12012/1, MC_UU_12012/5] Funding Source: UKRI
- British Heart Foundation [PG/07/085/23349, FS/11/35/28871] Funding Source: researchfish
- Cancer Research UK [11906, 22310] Funding Source: researchfish
- Medical Research Council [MC_UU_12012/5, G0600717, G0600717B, MC_UU_12012/5/B, MC_UU_12012/1, MR/K501050/1] Funding Source: researchfish
- Wellcome Trust [085686/Z/08/A] Funding Source: Wellcome Trust
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(1,2). 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(3). We performed exome sequencing of ten zona glomerulosa-like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na+/K+ ATPase alpha 1 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.
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