European journal of endocrinology · 2026
Recurrent CACNA1HE282K is a gain-of-function mutation associated with primary hyperaldosteronism.
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Li Ruyi, Jiang Yiran, Chen Qiujing, Zhao Yaxue, Lu Kechen, Nie Aifang, Zhang Cui, Su Tingwei, Jiang Lei, Zhou Weiwei, Zhong Xu, Wu Luming, Han Rulai, Ye Lei, Wang Weiqing
Аннотация
CONTEXT: Germline CACNA1H mutations have been associated with primary aldosteronism (PA). Here, we described 3 newly discovered CACNA1H variants and explored the possible pathogenic mechanisms as well as therapeutic strategies.
DESIGN: Targeted next-generation sequencing of 10 PA causative genes was performed in 305 PA patients. Variants with possible clinical significance in CACNA1H were identified. Functional analysis was performed in vitro including electrophysiology, steroid hormone production, and transcriptome. Responses to mibefradil and nifedipine were evaluated.
RESULTS: We described 3 heterozygous germline CACNA1H variants (E282K, V213M, and S1249R) in 4 independent cases of PA. Recurrent E282K mutation was identified in 1 patient with severe early-onset PA and 1 patient with bilateral adrenal hyperplasia (BAH). Electrophysiological analysis of mutant Cav3.2 channels revealed significant gain-of-function changes in the voltage-dependent activation and Ca2+ current properties for Cav3.2E282K, while ambiguous for Cav3.2S1249R and Cav3.2V213M. Moreover, stable expression of the 3 CACNA1H variants in H295R cells led to increased aldosterone production and upregulated expression of genes involved in steroidogenic enzymes, both basally and after K+ treatment. T-type calcium channel blocker showed more significant inhibition of aldosterone production in mutant Cav3.2 cells compared to L-type calcium channel blocker.
CONCLUSIONS: Our study suggests that Cav3.2E282K is a gain-of-function mutation and T-type calcium channel blockers may be efficient in controlling aldosterone levels for PA patients carrying mutant Cav3.2.
DESIGN: Targeted next-generation sequencing of 10 PA causative genes was performed in 305 PA patients. Variants with possible clinical significance in CACNA1H were identified. Functional analysis was performed in vitro including electrophysiology, steroid hormone production, and transcriptome. Responses to mibefradil and nifedipine were evaluated.
RESULTS: We described 3 heterozygous germline CACNA1H variants (E282K, V213M, and S1249R) in 4 independent cases of PA. Recurrent E282K mutation was identified in 1 patient with severe early-onset PA and 1 patient with bilateral adrenal hyperplasia (BAH). Electrophysiological analysis of mutant Cav3.2 channels revealed significant gain-of-function changes in the voltage-dependent activation and Ca2+ current properties for Cav3.2E282K, while ambiguous for Cav3.2S1249R and Cav3.2V213M. Moreover, stable expression of the 3 CACNA1H variants in H295R cells led to increased aldosterone production and upregulated expression of genes involved in steroidogenic enzymes, both basally and after K+ treatment. T-type calcium channel blocker showed more significant inhibition of aldosterone production in mutant Cav3.2 cells compared to L-type calcium channel blocker.
CONCLUSIONS: Our study suggests that Cav3.2E282K is a gain-of-function mutation and T-type calcium channel blockers may be efficient in controlling aldosterone levels for PA patients carrying mutant Cav3.2.