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Open Access | 10.1172/jci.insight.162100
1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Ortner, N.
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Sah, A.
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Carbone, E.
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Singewald, N.
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Roeper, J.
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1Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
2Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
3Institute for Neurophysiology, Goethe University, Frankfurt, Germany
4Department of Drug Science, N.I.S. Centre, University of Torino, Torino, Italy
5Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
6Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Published September 12, 2023 - More info
Germline de novo missense variants of the CACNA1D gene, encoding the pore-forming α1-subunit of Cav1.3 L-type Ca2+ channels (LTCCs), have been found in patients with neurodevelopmental and endocrine dysfunction, but their disease-causing potential is unproven. These variants alter channel gating enabling enhanced Cav1.3 activity, suggesting Cav1.3 inhibition as a potential therapeutic option. Here we provide direct proof of the disease-causing nature of such gating-modifying CACNA1D variants using mice (Cav1.3AG) containing the A749G variant reported de novo in a patient with autism and intellectual impairment. In heterozygous mutants native LTCC currents in adrenal chromaffin cells exhibited gating changes as predicted from heterologous expression. The A749G mutation induced aberrant excitability of dorsomedial striatum-projecting substantia nigra dopamine neurons and medium spiny neurons in the dorsal striatum. The phenotype observed in heterozygous mutants reproduced many of the abnormalities described within the human disease spectrum, including developmental delay, social deficit and pronounced hyperactivity without major changes in gross neuroanatomy. Despite an ~7-fold higher sensitivity of A749G-containing channels to the LTCC inhibitor isradipine, oral pretreatment over two days did not rescue the hyperlocomotion. Cav1.3AG mice confirm the pathogenicity of the A749G variant and point towards a pathogenetic role of altered signaling in the dopamine midbrain system.