Mutations of the Twik-Related Acid-Sensitive K+ Channel 2 Promoter in Human Primary Aldosteronism

• DOI: 10.1210/en.2017-03119
• Publication Date: 2017-12-26T19:05:08Z
• Authors: Livia Lenzini; Selene Prisco; Michele Gallina; Maniselvan Kuppusamy; Gian Paolo Rossi
• Keywords: Adult; Male; 0303 health sciences; Binding Sites; Sequence Analysis, DNA; Middle Aged; 3. Good health; 03 medical and health sciences; Potassium Channels, Tandem Pore Domain; Adrenocortical Adenoma; Hyperaldosteronism; Hypertension; Mutation; Humans; Female; Promoter Regions, Genetic; Aldosterone; Germ-Line Mutation; Transcription Factors

Because blunted expression of the twik-related acid-sensitive K+ channel 2 (TASK-2) is a common feature of aldosterone-producing adenoma (APA) causing primary aldosteronism (PA), we sequenced the promoter region of the TASK-2 gene (KCNK5) in APAs (n = 76), primary hypertensive patients (n = 98), and 20-year-old healthy volunteers (n = 71), searching for variants that could affect expression of this channel. We found TASK-2 promoter mutations in 25% of the APAs: C999T in 6.6%, G595A in 5.3%, G36A in 5.3%, and C562T, Gins468, G265C, C1247T, G1140T, and C1399T in 1.3% each. The C999T mutation was found in only one of the 98 primary hypertensive patients, but mutations were detected also in 12% of volunteers: 4 carried the C999T, 3 G1288C, 1 the G1140T mutation, and 1 the 468ins mutation. After a 16-year follow-up, none of these patients developed hypertension or PA. The effect of C999T mutation was investigated in H295R cells using reporter vectors with the mutated or the wild-type (WT) TASK-2 promoters. TASK-2 gene expression was decreased by 31% ± 18% (P = 0.01) in mutated compared with WT APA. Likewise, in transfected H295R cells, the C999T mutation decreased TASK-2 transcriptional activity by 35% (normalized luciferase signal fold change: 0.65 ± 0.25, P < 0.001). Thus, mutations in the promoter region of the TASK-2 gene can account for the low expression in ∼25% of APAs. As they did not result in hypertension or PA during long-term follow-up in healthy participants, these mutations do not seem to be a factor in causing PA by themselves.