van Rooyen Desmaré, Bandulik Sascha, Coon Grace A, Laukemper Miriam, Kumar-Sinha Chandan, Udager Aaron M, Lerario Antonio M, Lee Chaelin, Wachtel Heather, Cohen Debbie L, Luther James M, Giordano Thomas J, Scholl Ute I, Butz Frederike, Popp Bernt, Turcu Adina F, Warth Richard, Rainey William E, Rege Juilee
University of Michigan, Ann Arbor (D.v.R., G.A.C., C.K.-S., A.M.U., A.M.L., C.L., T.J.G., A.F.T., W.E.R., J.R.).
University of Regensburg, Germany (S.B., M.L., R.W.).
Hypertension. 2025 Aug 7. doi: 10.1161/HYPERTENSIONAHA.125.24909.
Primary aldosteronism is a common but underdiagnosed cause of endocrine hypertension that contributes to global cardiovascular morbidity and mortality. It is characterized by renin-independent hyperaldosteronism that originates from adrenal lesions-the majority of which are found to harbor aldosterone-driver somatic mutations in genes encoding ion-transporting proteins. These mutations disrupt intracellular calcium homeostasis, facilitating a pathological increase in aldosterone synthase expression and aldosterone production. Elucidating the exact mechanisms causing aldosterone excess in primary aldosteronism would further the development of targeted treatments and alleviate the global hypertension burden.
Next-generation sequencing analysis of formalin-fixed paraffin-embedded aldosterone-producing adenomas identified novel somatic variants in (encoding the cation-permeable channel, TRPML3). Electrophysiological, fura-2 calcium measurements, gene expression, and steroid quantification studies were performed in adrenal HAC15 cells to characterize the functional effects of the novel mutations.
Three somatic variants (p.Y391D, p.F415I, and p.N411_V412delinsI) were identified in aldosterone-producing adenomas from 4 male primary aldosteronism patients. Mutated expressed in HAC15 cells resulted in a gain-of-function phenotype, which induced cell membrane depolarization and calcium influx and, in turn, triggered a significant increase in aldosterone synthase expression and aldosterone production.
This is the first report of disease-causing mutations in humans and the first to implicate mutated as a driver of dysregulated aldosterone production in primary aldosteronism.
原发性醛固酮增多症是内分泌性高血压常见但诊断不足的病因，会导致全球心血管疾病的发病率和死亡率上升。其特征是肾素非依赖性醛固酮增多症，源于肾上腺病变，其中大多数被发现携带编码离子转运蛋白的基因中的醛固酮驱动体细胞突变。这些突变破坏细胞内钙稳态，促进醛固酮合酶表达和醛固酮产生的病理性增加。阐明原发性醛固酮增多症中醛固酮过量的确切机制将推动靶向治疗的发展并减轻全球高血压负担。
对福尔马林固定石蜡包埋的醛固酮瘤进行二代测序分析，在（编码阳离子通透通道，TRPML3）中鉴定出新的体细胞变体。在肾上腺HAC15细胞中进行电生理、fura-2钙测量、基因表达和类固醇定量研究，以表征新的突变的功能效应。
在4例男性原发性醛固酮增多症患者的醛固酮瘤中鉴定出3种体细胞变体（p.Y391D、p.F415I和p.N411_V412delinsI）。在HAC15细胞中表达的突变导致功能获得性表型，诱导细胞膜去极化和钙内流，进而引发醛固酮合酶表达和醛固酮产生的显著增加。
这是人类致病突变的首次报告，也是首次表明突变是原发性醛固酮增多症中醛固酮产生失调的驱动因素。
