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ResearchIn-Press PreviewNeuroscience Open Access | 10.1172/jci.insight.162100

The human channel gating-modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome-like phenotype in mice

Nadine J. Ortner,1 Anupam Sah,1 Enrica Paradiso,2 Josef Shin,3 Strahinja Stojanovic,3 Niklas Hammer,3 Maria Haritonova,1 Nadja T. Hofer,1 Andrea Marcantoni,4 Laura Guarina,4 Petronel Tuluc,1 Tamara Theiner,1 Florian Pitterl,5 Karl Ebner,1 Herbert Oberacher,5 Emilio Carbone,4 Nadia Stefanova,6 Francesco Ferraguti,2 Nicolas Singewald,1 Jochen Roeper,3 and Joerg Striessnig1

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

Find articles by Theiner, T. in: JCI | PubMed | Google Scholar

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

Find articles by Carbone, E. in: JCI | PubMed | Google Scholar |

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

Find articles by Stefanova, N. in: JCI | PubMed | Google Scholar |

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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Published September 12, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.162100.
Copyright © 2023, Ortner et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 12, 2023 - Version history
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Abstract

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.

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