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Open Access | 10.1172/jci.insight.162468
1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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Stölting, G.
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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Dinh, H.
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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Schewe, J.
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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Zhang, J.
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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Lifton, R.
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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Nottoli, T.
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1Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2Institute of Legal Medicine and Core Facility Metabolomics, Innsbruck Medical University, Innsbruck, Austria
3Nephrology, Yale University School of Medicine, New Haven, United States of America
4Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, United States of America
5Transgenic Technologies, Charité - Universitätsmedizin Berlin, Berlin, Germany
6Animal Outcome Core Facility, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin, Germany
7Yale Gene Editing Center, Yale University School of Medicine, New Haven, United States of America
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Scholl, U.
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Published September 12, 2023 - More info
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 (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 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.