A novel somatic CACNA1H p.V1937M mutation was identified as a pathogenic driver in aldosterone overproduction, demonstrating increased CYP11B2 expression in vitro and complete biochemical success 12 months after adrenalectomy.
Case Report (n=1)
Does the somatic CACNA1H p.V1937M mutation drive aldosterone overproduction in unilateral primary hyperaldosteronism?
The identification of the somatic CACNA1H p.V1937M mutation provides a novel pathogenic driver for aldosterone overproduction in unilateral primary hyperaldosteronism.
Background Somatic mutations for excess aldosterone production have been frequently identified as important roles in the pathogenesis of unilateral primary hyperaldosteronism (uPA). Although CACNA1H mutation represents a minor etiology in primary aldosteronism, it plays a significant role in causing uPAs in sporadic cases. Objective To identify novel somatic CACNA1H mutation in patients with uPA and investigate the pathophysiological, immunohistological, and clinical characteristics of the variant. Methods 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 in vitro studies, demonstrating aldosterone production in variant-transfected human adrenal cell lines. Results We identified a novel somatic CACNA1H mutation c.5809GA (p.Val1937Met) in a uPA case. The CACNA1H gene encodes the pore-forming alpha-1H subunit of the voltage-dependent T-type calcium channel Cav3.2. This somatic CACNA1H p.V1937M variant showed excellent clinical and biochemical outcomes after ipsilateral adrenalectomy. The functional effect of somatic CACNA1H 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. Conclusions The somatic mutation of CACNA1H p.V1937M might be a pathogenic driver in aldosterone overproduction. This study provides new insight into the molecular mechanism and disease outcomes of uPA.
Tseng et al. (Thu,) conducted a case report in Unilateral Primary Hyperaldosteronism (n=1). CACNA1H p.V1937M somatic mutation vs. Wild-type CACNA1H (in vitro) was evaluated on Clinical and biochemical success after adrenalectomy, and in vitro aldosterone biosynthesis. A novel somatic CACNA1H p.V1937M mutation was identified as a pathogenic driver in aldosterone overproduction, demonstrating increased CYP11B2 expression in vitro and complete biochemical success 12 months after adrenalectomy.