ArticleBiological psychiatry2015
CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels.
Article in Biological psychiatry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 118 papers, 2 of them syntheses that pooled it.
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Who cites it
118 citing papers in PubMed, 2 syntheses or guidelines pooled it, 187 citations in OpenAlex.
- Calcium channelopathies and intellectual disability: a systematic review.Orphanet journal of rare diseases · 2021Pooled it
- Genetic associations between voltage-gated calcium channels and autism spectrum disorder: a systematic review.Molecular brain · 2020Pooled it
- Identification of novel functional sites in the CaProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Temperature-dependent functional inversion of CaMolecular brain · 2026Article
- PASNA syndrome with overlappingJCEM case reports · 2026Article
- Calmodulinopathy variants impair CaV1.3 and CaV2.1 regulation.The Journal of general physiology · 2026Article
- Successful bilateral electroconvulsive therapy for catatonia presenting with novel climbing behavior in an adolescent withFrontiers in psychiatry · 2026Article
- Cerebral blood flow changes and their genetic mechanisms in autism spectrum disorder: a combined neuroimaging and transcriptome study.European archives of psychiatry and clinical neuroscience · 2025Article
- Deletion of the Voltage-Gated Calcium Channel Gene, CaCerebellum (London, England) · 2025Article
- Transcriptional Consequences of MeCP2 Knockdown and Overexpression in Mouse Primary Cortical Neurons.International journal of molecular sciences · 2025Article
- Transcriptomic Profiling of Zebrafish Mutant forInternational journal of molecular sciences · 2025Article
- Gating of hair cell CaScience advances · 2025Article
- Role of Cav1.3 Channels in Brain-Heart Interactions: An Unexpected Journey.Biomedicines · 2025Review
- Article
- Inactivation of CaV1 and CaV2 channels.The Journal of general physiology · 2025Review
- Synapse-to-Nucleus ERK→CREB Transcriptional Signaling Requires Dendrite-to-Soma CaThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- A Novel De Novo Gain-of-FunctionNeurology. Genetics · 2024Article
- The L-type calcium channel CaV1.3: A potential target for cancer therapy.Journal of cellular and molecular medicine · 2024Review
- Pathogenicity of de novo CACNA1D CaEuropean journal of human genetics : EJHG · 2024Article
- CaCell reports · 2024Article
58 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundCav1.3 voltage-gated L-type calcium channels (LTCCs) are part of postsynaptic neuronal signaling networks. They play a key role in brain function, including fear memory and emotional and drug-taking behaviors. A whole-exome sequencing study identified a de novo mutation, p.A749G, in Cav1.3 α1-subunits (CACNA1D), the second main LTCC in the brain, as 1 of 62 high risk-conferring mutations in a cohort of patients with autism and intellectual disability. We screened all published genetic information available from whole-exome sequencing studies and identified a second de novo CACNA1D mutation, p.G407R. Both mutations are present only in the probands and not in their unaffected parents or siblings.
methodsWe functionally expressed both mutations in tsA-201 cells to study their functional consequences using whole-cell patch-clamp.
resultsThe mutations p.A749G and p.G407R caused dramatic changes in channel gating by shifting (~15 mV) the voltage dependence for steady-state activation and inactivation to more negative voltages (p.A749G) or by pronounced slowing of current inactivation during depolarizing stimuli (p.G407R). In both cases, these changes are compatible with a gain-of-function phenotype.
conclusionsOur data, together with the discovery that Cav1.3 gain-of-function causes primary aldosteronism with seizures, neurologic abnormalities, and intellectual disability, suggest that Cav1.3 gain-of-function mutations confer a major part of the risk for autism in the two probands and may even cause the disease. Our findings have immediate clinical relevance because blockers of LTCCs are available for therapeutic attempts in affected individuals. Patients should also be explored for other symptoms likely resulting from Cav1.3 hyperactivity, in particular, primary aldosteronism.
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