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A Novel Method: Super-selective Adrenal Venous Sampling
Published on: September 15, 2017
Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension
Elena A B Azizan1, Hanne Poulsen, Petronel Tuluc
1Clinical 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.
Insights
Adrenal aldosterone-producing adenomas (APAs) with distinct genetic mutations were identified. These mutations in ATP1A1 or CACNA1D may lead to smaller tumors that are often missed by imaging, impacting hypertension diagnosis.
Area of Science:
- Endocrinology
- Genetics
- Molecular Biology
Background:
- Adrenal aldosterone-producing adenomas (APAs) are a significant cause of secondary hypertension.
- Known genetic mutations, such as in KCNJ5, are associated with specific APA subtypes.
- A subset of APAs, resembling adrenal zona glomerulosa cells, lacks common KCNJ5 mutations.
Purpose of the Study:
- To investigate the genetic basis of zona glomerulosa-like APAs.
- To identify novel mutations in APAs that may be overlooked in conventional diagnosis.
Main Methods:
- Exome sequencing was performed on ten zona glomerulosa-like APAs.
- Functional analysis of identified mutations in ATP1A1 and CACNA1D.
Main Results:
- Nine out of ten zona glomerulosa-like APAs harbored somatic mutations in ATP1A1 or CACNA1D.
- ATP1A1 mutations resulted in inward leak currents.
- CACNA1D mutations altered voltage-dependent gating and ion channel function.
- Many APAs with these mutations were small (<1 cm) and potentially missed by imaging.
Conclusions:
- Zona glomerulosa-like APAs have a distinct genetic profile involving ATP1A1 and CACNA1D mutations.
- These genetic findings are associated with specific functional alterations in ion transport.
- The small size of these APAs may explain why they are often overlooked, highlighting the need for improved diagnostic approaches.
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