ArticlePloS one2014
A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 2 syntheses or guidelines pooled it, 56 citations in OpenAlex.
- Geno- and phenotypic characteristics and clinical outcomes ofFrontiers in cardiovascular medicine · 2022Pooled it
- Calcium channelopathies and intellectual disability: a systematic review.Orphanet journal of rare diseases · 2021Pooled it
- Association between CACNA1C gene polymorphisms and ritodrine-induced adverse events in preterm labor patients.European journal of clinical pharmacology · 2017Trial
- Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease.Circulation. Cardiovascular genetics · 2015Trial
- Biphasic effects on human atrial arrhythmogenicity of L-type calcium channel mutations associated with a Brugada/Short QT overlap syndrome - insights from a multiscale simulation study.PLoS computational biology · 2025Article
- Using a Failing Human Ventricular Cardiomyocyte Model to Re-Evaluate CaBiomolecules · 2024Article
- Structural bases of inhibitory mechanism of CaNature communications · 2024Article
- Disruption of mitochondrial and lysosomal functions by humanFrontiers in molecular neuroscience · 2023Article
- CACNA1C-Related Channelopathies.Handbook of experimental pharmacology · 2023Review
- Increased CaScientific reports · 2022Article
- Novel CACNA1C R511Q mutation, located in domain Ⅰ-Ⅱ linker, causes non-syndromic type-8 long QT syndrome.PloS one · 2022Article
- Voltage-Gated CaFrontiers in synaptic neuroscience · 2021Review
- Update on the Molecular Genetics of Timothy Syndrome.Frontiers in pediatrics · 2021Review
- Aortic Valve Stenosis and Mitochondrial Dysfunctions: Clinical and Molecular Perspectives.International journal of molecular sciences · 2020Review
- Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside.Experimental biology and medicine (Maywood, N.J.) · 2019Article
- Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy.Molecular genetics & genomic medicine · 2019Article
- The genetic architecture of long QT syndrome: A critical reappraisal.Trends in cardiovascular medicine · 2018Review
- Role of a conserved glutamine in the function of voltage-gated CaThe Journal of biological chemistry · 2018Article
- Temporal Lobe Epilepsy, Stroke, and Traumatic Brain Injury: Mechanisms of Hyperpolarized, Depolarized, and Flow-Through Ion Channels Utilized as Tri-Coordinate Biomarkers of Electrophysiologic Dysfunction.OBM neurobiology · 2018Article
- Role of CACNA1C gene polymorphisms and protein expressions in the pathogenesis of schizophrenia: a case-control study in a Chinese population.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2017Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
Mutations in CACNA1C that increase current through the CaV1.2 L-type Ca2+ channel underlie rare forms of long QT syndrome (LQTS), and Timothy syndrome (TS). We identified a variant in CACNA1C in a male child of Filipino descent with arrhythmias and extracardiac features by candidate gene sequencing and performed functional expression studies to electrophysiologically characterize the effects of the variant on CaV1.2 channels. As a baby, the subject developed seizures and displayed developmental delays at 30 months of age. At age 5 years, he displayed a QTc of 520 ms and experienced recurrent VT. Physical exam at 17 years of age was notable for microcephaly, short stature, lower extremity weakness and atrophy with hyperreflexia, spastic diplegia, multiple dental caries and episodes of rhabdomyolysis. Candidate gene sequencing identified a G>C transversion at position 5731 of CACNA1C (rs374528680) predicting a glycine>arginine substitution at residue 1911 (p.G1911R) of CaV1.2. The allele frequency of this variant is 0.01 in Malays, but absent in 984 Caucasian alleles and in the 1000 genomes project. In electrophysiological analyses, the variant decreased voltage-dependent inactivation, thus causing a gain of function of CaV1.2. We also observed a negative shift of V1/2 of activation and positive shift of V1/2 of channel inactivation, resulting in an increase of the window current. Together, these suggest a gain-of-function effect on CaV1.2 and suggest increased susceptibility for arrhythmias in certain clinical settings. The p.G1911R variant was also identified in a case of sudden unexplained infant death (SUID), for which an increasing number of clinical observations have demonstrated can be associated with arrhythmogenic mutations in cardiac ion channels. In summary, the combined effects of the CACNA1C variant to diminish voltage-dependent inactivation of CaV1.2 and increase window current expand our appreciation of mechanisms by which a gain of function of CaV1.2 can contribute to QT prolongation.
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Registered trials
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.