Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 33; pp. E4591 - E4599
• Main Authors: Nishimoto, Koshiro, Tomlins, Scott A., Kuick, Rork, Cani, Andi K., Giordano, Thomas J., Hovelson, Daniel H., Liu, Chia-Jen, Sanjanwala, Aalok R., Edwards, Michael A., Gomez-Sanchez, Celso E., Nanba, Kazutaka, Rainey, William E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.08.2015; National Acad Sciences
• Series: PNAS Plus
• Subjects: Adrenal Cortex - metabolism; Adrenal glands; Adrenal Glands - metabolism; Aldosterone - biosynthesis; Biological Sciences; Calcium channels; Cytochrome P-450 CYP11B2 - metabolism; DNA - chemistry; Gene expression; Gene Expression Regulation; High-Throughput Nucleotide Sequencing; Homeostasis; Humans; Hyperaldosteronism - etiology; Hypertension; Mutation; Oligonucleotide Array Sequence Analysis; PNAS Plus; Principal Component Analysis; Sequence Analysis, DNA; Sequence Analysis, RNA; Transcriptome; Zona Glomerulosa; somatic mutations; aldosterone-producing cell cluster; adrenal; aldosterone; primary aldosteronism
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1505529112

Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosterone-producing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APArelated aldosterone-stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations incalcium channel, voltage-dependent, L-type, α1D-subunit(CACNA1D; 6 of 23 APCCs) andATPase, Na⁺/K⁺ transporting, α1-polypeptide(ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosterone-driving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA.