The human channel gating–modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome–like phenotype in mice
Germline de novo missense variants of the CACNA1D gene, encoding the pore-forming α1 subunit of Cav1.3 L-type Ca(2+) channels (LTCCs), have been found in patients with neurodevelopmental and endocrine dysfunction, but their disease-causing potential is unproven. These variants alter channel gating,...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619503/ https://www.ncbi.nlm.nih.gov/pubmed/37698939 http://dx.doi.org/10.1172/jci.insight.162100 |
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author | Ortner, Nadine J. Sah, Anupam Paradiso, Enrica Shin, Josef Stojanovic, Strahinja Hammer, Niklas Haritonova, Maria Hofer, Nadja T. Marcantoni, Andrea Guarina, Laura Tuluc, Petronel Theiner, Tamara Pitterl, Florian Ebner, Karl Oberacher, Herbert Carbone, Emilio Stefanova, Nadia Ferraguti, Francesco Singewald, Nicolas Roeper, Jochen Striessnig, Jörg |
author_facet | Ortner, Nadine J. Sah, Anupam Paradiso, Enrica Shin, Josef Stojanovic, Strahinja Hammer, Niklas Haritonova, Maria Hofer, Nadja T. Marcantoni, Andrea Guarina, Laura Tuluc, Petronel Theiner, Tamara Pitterl, Florian Ebner, Karl Oberacher, Herbert Carbone, Emilio Stefanova, Nadia Ferraguti, Francesco Singewald, Nicolas Roeper, Jochen Striessnig, Jörg |
author_sort | Ortner, Nadine J. |
collection | PubMed |
description | Germline de novo missense variants of the CACNA1D gene, encoding the pore-forming α1 subunit of Cav1.3 L-type Ca(2+) 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 proof of the disease-causing nature of such gating-modifying CACNA1D variants using mice (Cav1.3(AG)) containing the A749G variant reported de novo in a patient with autism spectrum disorder (ASD) 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 approximately 7-fold higher sensitivity of A749G-containing channels to the LTCC inhibitor isradipine, oral pretreatment over 2 days did not rescue the hyperlocomotion. Cav1.3(AG) mice confirm the pathogenicity of the A749G variant and point toward a pathogenetic role of altered signaling in the dopamine midbrain system. |
format | Online Article Text |
id | pubmed-10619503 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-106195032023-11-02 The human channel gating–modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome–like phenotype in mice Ortner, Nadine J. Sah, Anupam Paradiso, Enrica Shin, Josef Stojanovic, Strahinja Hammer, Niklas Haritonova, Maria Hofer, Nadja T. Marcantoni, Andrea Guarina, Laura Tuluc, Petronel Theiner, Tamara Pitterl, Florian Ebner, Karl Oberacher, Herbert Carbone, Emilio Stefanova, Nadia Ferraguti, Francesco Singewald, Nicolas Roeper, Jochen Striessnig, Jörg JCI Insight Research Article Germline de novo missense variants of the CACNA1D gene, encoding the pore-forming α1 subunit of Cav1.3 L-type Ca(2+) 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 proof of the disease-causing nature of such gating-modifying CACNA1D variants using mice (Cav1.3(AG)) containing the A749G variant reported de novo in a patient with autism spectrum disorder (ASD) 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 approximately 7-fold higher sensitivity of A749G-containing channels to the LTCC inhibitor isradipine, oral pretreatment over 2 days did not rescue the hyperlocomotion. Cav1.3(AG) mice confirm the pathogenicity of the A749G variant and point toward a pathogenetic role of altered signaling in the dopamine midbrain system. American Society for Clinical Investigation 2023-10-23 /pmc/articles/PMC10619503/ /pubmed/37698939 http://dx.doi.org/10.1172/jci.insight.162100 Text en © 2023 Ortner et al. https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Ortner, Nadine J. Sah, Anupam Paradiso, Enrica Shin, Josef Stojanovic, Strahinja Hammer, Niklas Haritonova, Maria Hofer, Nadja T. Marcantoni, Andrea Guarina, Laura Tuluc, Petronel Theiner, Tamara Pitterl, Florian Ebner, Karl Oberacher, Herbert Carbone, Emilio Stefanova, Nadia Ferraguti, Francesco Singewald, Nicolas Roeper, Jochen Striessnig, Jörg The human channel gating–modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome–like phenotype in mice |
title | The human channel gating–modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome–like phenotype in mice |
title_full | The human channel gating–modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome–like phenotype in mice |
title_fullStr | The human channel gating–modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome–like phenotype in mice |
title_full_unstemmed | The human channel gating–modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome–like phenotype in mice |
title_short | The human channel gating–modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome–like phenotype in mice |
title_sort | human channel gating–modifying a749g cacna1d (cav1.3) variant induces a neurodevelopmental syndrome–like phenotype in mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619503/ https://www.ncbi.nlm.nih.gov/pubmed/37698939 http://dx.doi.org/10.1172/jci.insight.162100 |
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