Endocrine Abstracts (2012) 28 S11.2

Human Potassium channel mutations and mineralocorticoid hypertension

Maria-Christina Zennaro1,2,3

1U970, Paris Cardiovascular Research Center, INSERM, Paris, France; 2University Paris Descartes, Paris, France; 3Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.

Primary aldosteronism (PA) is the most common form of secondary hypertension with an estimated prevalence between 6 and 12% of hypertensives and as high as 20% in patients with resistant hypertension. Among subtypes of PA, the two principal causes are Aldosterone Producing Adenoma (APA) and Bilateral Adrenal Hyperplasia (BAH, also known as idiopathic hyperaldosteronism). Recent evidence has suggested that recurrent somatic mutations of the KCNJ5 gene coding for the potassium channel Kir3.4 could account for a substantial proportion of APA, but also that a similar germinal KCNJ5 mutation causes a very rare autosomal dominant and early-onset form of PA, characterized by bilateral massive adrenal hyperplasia and referred to as FH-3. Investigation of a large number of patients recruited from reference centers organized within the European Network for the Study of Adrenal Tumors (ENS@T) has allowed us to demonstrate that somatic KCNJ5 mutations are found in more than one third of patients with APA. Importantly, similar germinal mutations are not responsible for BAH. Mutations are significantly more prevalent in females and in younger patients of both genders and appear to be associated with a more florid phenotype of PA, but not to therapeutic outcome after surgery. Somatic KCNJ5 mutations appear to be isolated events in the progression towards APA and specific for the disease, as they are not found in peritumoral adrenal tissue or cortisol producing adenomas. Interestingly, the lack of a specific transcriptome profile in APA carrying KCNJ5 mutations as compared to APA non carrying KCNJ5 mutations implies that abnormal Kir3.4 channel function represents one if several different possible mechanisms resulting in activation of calcium signaling in the zona glomerulosa, ultimately leading to autonomous aldosterone production and (possibly) cellular proliferation.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: This work was performed within the European Network for the Study of Adrenal Tumors (ENS@T) and has been supported by individual sources of funding attributed to each paticipating center. For the presenting author, the work was funded through institutional support from INSERM, by the Agence Nationale pour la Recherche (ANR Physio 2007, No.: 013-01), and the Fondation pour la Recherche sur l'Hypertension Artérielle (AO 2007).

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