Endocrine Abstracts

Primary aldosteronism (PA) accounts for the largest proportion of cases of secondary hypertension worldwide. The majority of PA cases are a result of a unilateral aldosterone-producing adenoma (APA). The pathogenesis of APAs, the most curable form of hypertension, has been the focus of worldwide clinical interest, and is associated with mutations in four genes: KCNJ5, ATP1A1, ATP2B3, and CACNA1D. Investigation into these mutations may lead to earlier detection, critical for a chronic condition in which the likelihood of a complete cure decreases with time.

Analysis of APA tissue often reveals a zona fasciculata (ZF)-like phenotype, based on cellular morphology, despite the zona glomerulosa (ZG)-restricted expression of CYP11B2, the enzyme required for aldosterone production, in normal tissue. Recently, it was demonstrated that ZG-like adenomas preferentially harbour mutations in ATP1A1 and CACNA1D, but ATP2B3 mutations were not identified¹. We collected samples from 36 patients. RT-PCR and Sanger sequencing identified mutations in KCNJ5 and ATP2B3, and these adenomas were stained with CYP11B1 and CYP11B2 antibodies to identify cellular phenotypes.

We confirmed that KCNJ5-mutant APAs are more common in women and are generally of a larger size than APAs with mutations in ATP1A1 and ATP2B3. Interestingly, our population of patients has a significantly greater prevalence of mutations in the ATP2B3 gene, 8.3%, and no mutations in ATP1A1, compared to the worldwide prevalences of 1.7 and 5.3% respectively.² Results from immunostaining indicate a complex relationship between genetic mutation and cell phenotype; one ATP2B3 mutation was CYP11B1 negative whereas one was positive, and a similar pattern for adenomas harbouring KCNJ5 mutations was observed, supporting the observations of others.² We hope further investigations will lead to a genotype–phenotype correlation, particularly regarding gender differences and adenoma size, and ultimately improved treatment options.

References: 1. Azizan et al. Nat Genet 2013 45 1055–1062.

2. Fernandes-Rosa et al. Hypertension 2014 64 354–361.