ArticleInternational journal of cardiology2016
Novel long QT syndrome-associated missense mutation, L762F, in CACNA1C-encoded L-type calcium channel imparts a slower inactivation tau and increased sustained and window current.
Article in International journal of cardiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.
- Geno- and phenotypic characteristics and clinical outcomes ofFrontiers in cardiovascular medicine · 2022Pooled it
- Timothy syndrome and CACNA1C-Related Disorder: first international language and management guidelines consensus statement.European journal of human genetics : EJHG · 2026Review
- Timothy Syndrome and CACNA1C-Related Disorder: First International Language and Management Guidelines Consensus Statement.Research square · 2025Article
- Calmodulin D133H Disrupts CaCells · 2025Article
- Inactivation of CaV1 and CaV2 channels.The Journal of general physiology · 2025Review
- Arrhythmogenic calmodulin variants D131E and Q135P disrupt interaction with the L-type voltage-gated CaActa physiologica (Oxford, England) · 2025Article
- Structural bases of inhibitory mechanism of CaNature communications · 2024Article
- Precision medicine for long QT syndrome: patient-specific iPSCs take the lead.Expert reviews in molecular medicine · 2023Review
- CaV1.2 channelopathic mutations evoke diverse pathophysiological mechanisms.The Journal of general physiology · 2022Article
- Novel CACNA1C R511Q mutation, located in domain Ⅰ-Ⅱ linker, causes non-syndromic type-8 long QT syndrome.PloS one · 2022Article
- Mechanisms underlying pathological CaPflugers Archiv : European journal of physiology · 2021Review
- Voltage-Gated CaFrontiers in synaptic neuroscience · 2021Review
- Variant R94C inJournal of the American Heart Association · 2020Article
- From Genome-Wide Association Studies to Cardiac Electrophysiology: Through the Maze of Biological Complexity.Frontiers in physiology · 2020Review
- Calcium Handling Defects and Cardiac Arrhythmia Syndromes.Frontiers in pharmacology · 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
- Gene and Protein Expression Profile of Selected Molecular Targets Mediating Electrophysiological Function inInternational journal of molecular sciences · 2018Article
- The genetic architecture of long QT syndrome: A critical reappraisal.Trends in cardiovascular medicine · 2018Review
- Ion Channel Disorders and Sudden Cardiac Death.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundMutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy syndrome (TS) with severe QT prolongation, syndactyly, facial dysmorphisms, developmental delay, and sudden death. Recently, patients hosting CACNA1C mutations with only long QT syndrome (LQTS) have been described. We sought to identify novel variants in CACNA1C associated with either TS or LQTS, and to determine the impact of the mutation on channel function. METHODS/
resultsTwo probands were identified with mutations in CACNA1C, one with a TS-associated mutation, G406R, and a second with genotype-negative LQTS. Illumina HiSeq 2000 whole exome sequencing on the genotype-negative LQTS proband revealed a novel variant, CACNA1C-L762F, that co-segregated within a multi-generational family. The missense mutation localized to the DII/DIII intracellular interlinker segment of the channel in a highly conserved region in close proximity to the 6th transmembrane segment of domain II (DIIS6). Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased sustained and window current. Comprehensive review and topological mapping of all described CACNA1C mutations revealed TS-specific hotspots localizing to the cytoplasmic aspect of 6th transmembrane segment of respective domains. Probands hosting TS mutations were associated with elevated QTc, higher prevalence of 2:1 AV block, and a younger age at presentation compared to LQTS.
conclusionsThe CACNA1C-L762F mutation is associated with development of LQTS through slower channel inactivation and increased sustained and window current. TS-associated mutations localize to specific areas of CACNA1C and are associated with a younger age at presentation, higher QTc, and 2:1 AV block than isolated LQTS-associated mutations.
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