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Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities
Gabriel Stölting1, Hoang An Dinh1, Marina Volkert1
1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
Abstract:
Somatic gain-of-function mutations in the L-type calcium channel CaV1.3 (CACNA1D gene) cause adrenal aldosterone-producing adenomas and micronodules. De novo germline mutations are found in a syndrome of primary aldosteronism, seizures, and neurologic abnormalities (PASNA) as well as in autism spectrum disorder. Using CRISPR/Cas9, we here generated mice with a Cacna1d gain-of-function mutation found in both adenomas and PASNA syndrome (Cacna1dIle772Met/+). These mice show reduced body weight and increased mortality from weaning to approximately 100 days of age. Male mice do not breed, likely due to neuromotor impairment, and the offspring of female mice die perinatally, likely due to lack of maternal care. Mice generated by in vitro fertilization showed elevated intracellular calcium in the aldosterone-producing zona glomerulosa, an elevated aldosterone/renin ratio, and persistently elevated serum aldosterone on a high-salt diet as signs of primary aldosteronism. Anesthesia with ketamine and xylazine induced tonic-clonic seizures. Neurologic abnormalities included hyperlocomotion, impaired performance in the rotarod test, impaired nest building, and slight changes in social behavior. Intracellular calcium in the zona glomerulosa, aldosterone levels, and rotarod performance responded to treatment with the calcium channel blocker isradipine, with implications for the therapy of patients with aldosterone-producing lesions and with PASNA syndrome.
Insights
Gain-of-function mutations in the CaV1.3 calcium channel (CACNA1D) cause primary aldosteronism and neurologic issues. Mouse models reveal disease mechanisms and potential therapeutic targets for related human syndromes.
Area of Science:
- Neuroscience
- Endocrinology
- Genetics
Background:
- Somatic gain-of-function mutations in the L-type calcium channel CaV1.3 (CACNA1D) are linked to adrenal aldosterone-producing adenomas.
- Germline mutations in CACNA1D cause primary aldosteronism, seizures, and neurologic abnormalities (PASNA) syndrome and autism spectrum disorder.
Purpose of the Study:
- To generate and characterize a mouse model with a Cacna1d gain-of-function mutation (Ile772Met/+) relevant to human diseases.
- To investigate the physiological and neurological consequences of this mutation in vivo.
Main Methods:
- CRISPR/Cas9 gene editing was used to create Cacna1d gain-of-function mutant mice.
- Phenotypic analysis included assessment of body weight, mortality, breeding success, in vitro fertilization, hormone levels, seizure susceptibility, and neurological tests (rotarod, nest building, social behavior).
Main Results:
- Mutant mice exhibited reduced body weight, increased mortality, and impaired breeding, with offspring mortality likely due to maternal care deficits.
- In vitro fertilization-derived mice showed elevated intracellular calcium in the zona glomerulosa, increased aldosterone/renin ratio, and persistently high serum aldosterone.
- Mice displayed tonic-clonic seizures under anesthesia, hyperlocomotion, impaired rotarod performance, and altered social behavior, all partially responsive to isradipine treatment.
Conclusions:
- The Cacna1d Ile772Met/+ mouse model recapitulates key features of primary aldosteronism and neurological abnormalities seen in PASNA syndrome.
- Calcium channel blocker isradipine shows therapeutic potential for both endocrine and neurological symptoms, suggesting a common pathogenic mechanism involving CaV1.3 channel dysfunction.
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