K001 Is primary aldosteronism a channelopathy ?

Abstract

In mouse models the genetic deletion of TWIK-related acid-sensitive K (TASK)-1 and TASK-3 channels removes an important background K current that results in a marked depolarization of adrenal zona glomerulosa cell membrane potential, leading to the autonomous overproduction of aldosterone. The importance of TASK channel dysfunction in human primary aldosteronism (PAL) however, is uncertain, motivating their molecular analysis. We screened coding exons and flanking intronic sequences of KCNK3 and KCNK9 (genes coding for TASK 1 and TASK 3 respectively) in 825 PAL patients for germline DNA sequence variants. A total of 14 different coding sequence variants were found in 19 patients. The variants include 8 different synonymous mutations and 6 different missense variants. In silico predictions (PolyPhen, SIFT and Alamut) suggested the non-synonymous mutations to be potentially damaging. Analysis of mutated channel function by heterologous expression, however, revealed the missense mutations detected were non-functional. As somatic mutations may be involved in some cases of sporadic PAL, sequencing 90 patients for tumoral DNA sequence variants is underway. We are also investigating expression of TASK 1 and TASK 3 by in-situ hybridization and immunohistochemistry on adrenal tissue sections of 150 PAL patients who have undergone surgery.