ArticleHuman molecular genetics2017
New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers, 3 of them syntheses that pooled it.
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Who cites it
69 citing papers in PubMed, 3 syntheses or guidelines pooled it, 125 citations in OpenAlex.
- A systematic review of non-coding RNA genes with differential expression profiles associated with autism spectrum disorders.PloS one · 2023Pooled it
- 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
- Thiazole-Substituted Benzoylpiperazines with Anti-Cancer and Anti-Inflammatory Activities: Comparative Evaluation with Lercanidipine.International journal of molecular sciences · 2026Article
- Identification of novel functional sites in the CaProceedings of the National Academy of Sciences of the United States of America · 2026Article
- A key gene modulating oxytocin efficacy in autism: genome-wide discovery and verification in randomized controlled trials datasets.Molecular psychiatry · 2026Article
- PRMT5-Cacna1d axis maintains calcium homeostasis to regulate postnatal motor development in mice.Cellular and molecular life sciences : CMLS · 2026Article
- Calmodulinopathy variants impair CaV1.3 and CaV2.1 regulation.The Journal of general physiology · 2026Article
- Genetic architecture and clinical features of Tourette syndrome in a child and adolescent cohort: an explorative clinical exome-based study.Frontiers in psychiatry · 2026Article
- Sclareol and cinnarizine are non-selective inhibitors of voltage-gated Cav1.3 L-type CaChannels (Austin, Tex.) · 2025Article
- Adrenal causes of endocrine hypertension in childhood or adolescence.Journal of endocrinological investigation · 2025Review
- Deletion of the Voltage-Gated Calcium Channel Gene, CaCerebellum (London, England) · 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
- Voltage-gated calcium channels in genetic epilepsies.Journal of neurochemistry · 2024Review
- 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
- Review
- Undiagnosed Disease Network collaborative approach in diagnosing rare disease in a patient with a mosaic CACNA1D variant.American journal of medical genetics. Part A · 2024Article
9 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 5 institutions in 2 countries.
Funding
Abstract
CACNA1D encodes the pore-forming α1-subunit of Cav1.3, an L-type voltage-gated Ca2+-channel. Despite the recent discovery of two de novo missense gain-of-function mutations in Cav1.3 in two individuals with autism spectrum disorder (ASD) and intellectual disability CACNA1D has not been considered a prominent ASD-risk gene in large scale genetic analyses, since such studies primarily focus on likely-disruptive genetic variants. Here we report the discovery and characterization of a third de novo missense mutation in CACNA1D (V401L) in a patient with ASD and epilepsy. For the functional characterization we introduced mutation V401L into two major C-terminal long and short Cav1.3 splice variants, expressed wild-type or mutant channel complexes in tsA-201 cells and performed whole-cell patch-clamp recordings. Mutation V401L, localized within the channel's activation gate, significantly enhanced current densities, shifted voltage dependence of activation and inactivation to more negative voltages and reduced channel inactivation in both Cav1.3 splice variants. Altogether, these gating changes are expected to result in enhanced Ca2+-influx through the channel, thus representing a strong gain-of-function phenotype. Additionally, we also found that mutant channels retained full sensitivity towards the clinically available Ca2+ -channel blocker isradipine. Our findings strengthen the evidence for CACNA1D as a novel candidate autism risk gene and encourage experimental therapy with available channel-blockers for this mutation. The additional presence of seizures and neurological abnormalities in our patient define a novel phenotype partially overlapping with symptoms in two individuals with PASNA (congenital primary aldosteronism, seizures and neurological abnormalities) caused by similar Cav1.3 gain-of-function mutations.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.