A Novel Somatic Mutation of CACNA1H p.V1937M in Unilateral Primary Hyperaldosteronism

Abstract

BackgroundSomatic 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.ObjectiveTo identify novel somatic CACNA1H mutation in patients with uPA and investigate the pathophysiological, immunohistological, and clinical characteristics of the variant.MethodsWe 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.ResultsWe identified a novel somatic CACNA1H mutation c.5809G>A (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.ConclusionsThe 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.

Primary aldosteronism: molecular medicine meets public health

“…A small subset of unilateral APAs have been reported to harbour recurrent somatic mutations in CACNA1H (Ile1430Thr, Val1937Met) 80 , 81 , in the same region as the germline mutations that cause FH type IV ( CACNA1H Met1549Val and Met1549Ile 82 ; Table 1 ). CACNA1H encodes the pore-forming α1H subunit of the voltage-dependent T-type calcium channel Ca v 3.2, which, similar to CACNA1D , is expressed in the adrenal ZG 82 .…”