Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Department of Urology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.
Front Endocrinol (Lausanne). 2022 Jun 9;13:816476. doi: 10.3389/fendo.2022.816476. eCollection 2022.
Somatic mutations for excess aldosterone production have been frequently identified as important roles in the pathogenesis of unilateral primary hyperaldosteronism (uPA). Although mutation represents a minor etiology in primary aldosteronism, it plays a significant role in causing uPAs in sporadic cases.
To identify novel somatic mutation in patients with uPA and investigate the pathophysiological, immunohistological, and clinical characteristics of the variant.
We applied a customized and targeted gene panel next-generation sequencing approach to detect mutations from the uPA cohort in Taiwan Primary Aldosteronism Investigation study group. Information from pre-diagnostic to postoperative data was collected, including past history, medications, blood pressure readings, biochemical data, and image studies. The functional role of the variant was confirmed by studies, demonstrating aldosterone production in variant-transfected human adrenal cell lines.
We identified a novel somatic mutation c.5809G>A (p.Val1937Met) in a uPA case. The gene encodes the pore-forming alpha-1H subunit of the voltage-dependent T-type calcium channel Cav3.2. This somatic p.V1937M variant showed excellent clinical and biochemical outcomes after ipsilateral adrenalectomy. The functional effect of somatic p.V1937M variant results in increased CYP11B2 expression and aldosterone biosynthesis in HAC15 cells. A distinct heterogeneous foamy pattern of CYP11B2 and CYP17A1 expression was identified in immunohistological staining, supporting the pathological evidence of aldosterone synthesis.
The somatic mutation of p.V1937M might be a pathogenic driver in aldosterone overproduction. This study provides new insight into the molecular mechanism and disease outcomes of uPA.
过量醛固酮产生的体细胞突变已被频繁确定为单侧原发性醛固酮增多症（uPA）发病机制中的重要作用。虽然 突变在原发性醛固酮增多症中代表次要病因，但它在散发性病例中导致 uPA 中起着重要作用。
鉴定 uPA 患者中新的体细胞 突变，并研究该变体的病理生理、免疫组织化学和临床特征。
我们应用定制的靶向基因 panel 下一代测序方法从台湾原发性醛固酮增多症研究组的 uPA 队列中检测突变。收集了从诊断前到术后的数据信息，包括既往病史、药物、血压读数、生化数据和影像学研究。通过 研究证实了变体的功能作用，表明变体转染的人肾上腺细胞系中醛固酮的产生。
我们在 uPA 病例中鉴定出一种新的体细胞 突变 c.5809G>A（p.Val1937Met）。该基因编码电压依赖性 T 型钙通道 Cav3.2 的 pore-forming alpha-1H 亚基。这种体细胞 p.V1937M 变体在同侧肾上腺切除术后显示出出色的临床和生化结果。体细胞 p.V1937M 变体的功能作用导致 CYP11B2 表达和醛固酮生物合成增加在 HAC15 细胞中。在免疫组织化学染色中鉴定出 CYP11B2 和 CYP17A1 表达的明显异质泡沫样模式，支持醛固酮合成的病理证据。
p.V1937M 的体细胞突变可能是醛固酮过度产生的致病驱动因素。本研究为 uPA 的分子机制和疾病结果提供了新的见解。
