Abstract
Studies on excised adrenals from primary aldosteronism patients have found that somatic mutations in KCNJ5 frequently cause excess aldosterone production in the culprit aldosterone-producing adenoma (APA). KCNJ5 mutant APAs were reported to be peculiarly overrepresented among young females and in Oriental cohorts, compared to their older male, or Caucasian counterparts. These larger APAs were also reported to have similarities with the zona fasciculata (ZF) in the adrenal both from the steroid production profile and the morphology of the cell. We therefore aimed to corroborate these findings by characterizing the APAs from a multi-ethnic Malaysian cohort. The prevalence of KCNJ5 mutations was estimated through targeted DNA sequencing of KCNJ5 in 54 APAs. Confirmation of APA sample acquisition was performed by CYP11B2 immunohistochemistry (IHC) staining. The ZF steroid production profile was based on the ZF enzyme CYP17A1 IHC staining, and ZF cell morphology was based on a high cytoplasm to nucleus ratio. Seventeen (31.5%) APAs studied, harbored a KCNJ5 mutation. No female over-representation was seen in this cohort though females were found to have a higher expression of CYP11B2 than males (p = 0.009; Mann-Whitney U test). Age at adrenalectomy correlated negatively with the percentage of ZF-like cells in the APA (p = 0.01; Spearman's rho) but not with the KCNJ5 genotype. KCNJ5 mutant APAs had a high percentage of ZF-like cells (and high CYP17A1 expression) but so did the wild-type APAs. In summary, prevalence of KCNJ5 mutant APAs in this cohort was similar to other Caucasian cohorts, however, over-representation of females did not occur, which is similar to some studies in Oriental cohorts.
Highlights
Primary aldosteronism (PA) is the most common cause of secondary hypertension, with an estimated prevalence of ∼10% among hypertensive patients and ∼20% among resistance hypertension [1,2,3,4,5,6]
There was no overrepresentation of females with KCNJ5 mutant aldosteroneproducing adenomas (APA) and there were no significant differences between the number of Malay patients and the number of Chinese patients that had a KCNJ5 mutant APA (Table 1)
Numerous studies performed on the excised tissues have found that a high prevalence of the KCNJ5 mutation to be the cause of this pathology [18,19,20, 34]
Summary
Primary aldosteronism (PA) is the most common cause of secondary hypertension, with an estimated prevalence of ∼10% among hypertensive patients and ∼20% among resistance hypertension [1,2,3,4,5,6]. Studies performed in excised APA tissues found functional somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 cause PA [11,12,13,14,15]. These aldosterone-driver mutations have been found in aldosterone-producing cell clusters (APCC) in normal adrenal glands [16] and in micronodular lesions [17]. The two most common somatic mutations in KCNJ5 are the G151R and L168R mutations located in or near the selectivity filter of this K+ channel [13] Presence of these mutations causes loss of the K+ channel selectivity leading to increased Na+ conductance, cell depolarization, and autonomous aldosterone production
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