CACNA1H – Primary Aldosteronism

CACNA1H encodes the pore-forming α1 subunit (CaV3.2) of T-type voltage-dependent calcium channels, highly expressed in adrenal glomerulosa cells. Pathogenic variants in CACNA1H underlie multiple forms of primary aldosteronism (PA), including familial hyperaldosteronism type IV (FH-IV) and aldosterone-producing adenomas (APAs).

Autosomal-dominant inheritance is supported by de novo and familial cases. To date, ten unrelated probands with germline CACNA1H variants have been reported: one de novo R890H ([PMID:31126930]), five M1549V in early-onset PA ([PMID:25907736]), and four additional heterozygous variants (S196Leu, Pro2083Leu, Val1951Glu, Met1549Ile) identified by exome sequencing ([PMID:27729216]). Somatic I1430T was found in APAs (3/75, 4%) ([PMID:31983310]).

Variant spectrum includes missense changes exclusively; no loss-of-function truncations have been described in PA. The predominant recurrent allele c.4645A>G (p.Met1549Val) has been observed in five unrelated early-onset PA cases. Somatic c.4289T>C (p.Ile1430Thr) occurs at low prevalence in APAs.

Functional assays demonstrate gain-of-function for M1549V and other PA mutations, with hyperpolarizing shifts in activation and slowed inactivation leading to increased intracellular Ca2+ and aldosterone production ([PMID:31706065]; [PMID:31983310]). Conversely, the de novo R890H variant causes reduced whole-cell current consistent with channel loss-of-function but nonetheless precipitates PA ([PMID:31126930]).

Together, these data indicate that both gain- and loss-of-function CACNA1H variants dysregulate adrenal Ca2+ signaling to drive autonomous aldosterone secretion. The mechanism appears allelic-specific but converges on enhanced CYP11B2 expression and hormone overproduction.

Key Take-home: CACNA1H should be included in genetic testing panels for early-onset or familial primary aldosteronism to guide diagnosis and inform management.

References

• BMJ Case Reports • 2019 • Primary aldosteronism associated with a germline variant in CACNA1H. PMID:31126930
• Hypertension • 2020 • Somatic CACNA1H Mutation As a Cause of Aldosterone-Producing Adenoma. PMID:31983310
• eLife • 2015 • Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. PMID:25907736
• EBioMedicine • 2016 • CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism. PMID:27729216
• Cell Calcium • 2019 • Splice-variant-specific effects of primary aldosteronism point mutations on human CaV3.2 calcium channels. PMID:31706065

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