Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities

Gabriel Stölting; Hoang An Dinh; Marina Volkert; Nicole Hellmig; Julia Schewe; Luise Hennicke; Eric Seidel; Herbert Oberacher; Junhui Zhang; Richard P. Lifton; Iris Urban; Melissa Long; Marion Rivalan; Timothy Nottoli; Ute I. Scholl

doi:10.1172/jci.insight.162468

Isradipine therapy in Cacna1d^Ile772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities

Gabriel Stölting,¹ Hoang An Dinh,¹ Marina Volkert,¹ Nicole Hellmig,¹ Julia Schewe,¹ Luise Hennicke,¹ Eric Seidel,¹ Herbert Oberacher,² Junhui Zhang,³ Richard P. Lifton,⁴ Iris Urban,⁵ Melissa Long,⁶ Marion Rivalan,⁶ Timothy Nottoli,⁷ and Ute I. Scholl¹

Published September 12, 2023 - More info

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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 disease. Using CRISPR/Cas9, we here generated mice with a Cacna1d gain-of-function mutation found in both adenomas and PASNA syndrome (Cacna1d^Ile772Met/+). 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 show 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 induces tonic-clonic seizures. Neurologic abnormalities include 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 respond to treatment with the calcium channel blocker isradipine, with implications for the therapy of patients with aldosterone-producing lesions and with PASNA syndrome.

Isradipine therapy in Cacna1d^Ile772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities

Gabriel Stölting,¹ Hoang An Dinh,¹ Marina Volkert,¹ Nicole Hellmig,¹ Julia Schewe,¹ Luise Hennicke,¹ Eric Seidel,¹ Herbert Oberacher,² Junhui Zhang,³ Richard P. Lifton,⁴ Iris Urban,⁵ Melissa Long,⁶ Marion Rivalan,⁶ Timothy Nottoli,⁷ and Ute I. Scholl¹

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Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities

Gabriel Stölting,1 Hoang An Dinh,1 Marina Volkert,1 Nicole Hellmig,1 Julia Schewe,1 Luise Hennicke,1 Eric Seidel,1 Herbert Oberacher,2 Junhui Zhang,3 Richard P. Lifton,4 Iris Urban,5 Melissa Long,6 Marion Rivalan,6 Timothy Nottoli,7 and Ute I. Scholl1

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Isradipine therapy in Cacna1d^Ile772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities

Gabriel Stölting,¹ Hoang An Dinh,¹ Marina Volkert,¹ Nicole Hellmig,¹ Julia Schewe,¹ Luise Hennicke,¹ Eric Seidel,¹ Herbert Oberacher,² Junhui Zhang,³ Richard P. Lifton,⁴ Iris Urban,⁵ Melissa Long,⁶ Marion Rivalan,⁶ Timothy Nottoli,⁷ and Ute I. Scholl¹