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Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):E4591-9. doi: 10.1073/pnas.1505529112. Epub 2015 Aug 3.

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

Author information

1
Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109;
2
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109; Department of Pathology, University of Michigan, Ann Arbor, MI 48109; Deparment of Urology, University of Michigan, Ann Arbor, MI 48109; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109;
3
Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109;
4
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109; Department of Pathology, University of Michigan, Ann Arbor, MI 48109;
5
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109; Department of Pathology, University of Michigan, Ann Arbor, MI 48109; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109;
6
Department of Surgery, Temple University School of Medicine, Philadelphia, PA 19140;
7
Division of Endocrinology, G. V. (Sonny) Montgomery Veterans Affairs Medical Center and University of Mississippi Medical Center, Jackson, MS 39110.
8
Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109; wer@umich.edu.

Abstract

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 APA-related 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 in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, 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.

KEYWORDS:

adrenal; aldosterone; aldosterone-producing cell cluster; primary aldosteronism; somatic mutations

PMID:
26240369
PMCID:
PMC4547250
DOI:
10.1073/pnas.1505529112
[Indexed for MEDLINE]
Free PMC Article

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