ArticleHeart rhythm2015
Novel Timothy syndrome mutation leading to increase in CACNA1C window current.
Article in Heart rhythm, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 3 of them syntheses that pooled it.
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Who cites it
54 citing papers in PubMed, 3 syntheses or guidelines pooled it, 92 citations in OpenAlex.
- Diagnosis and management of very rare primary arrhythmia syndromes in children and adults: a Clinical Consensus Statement of the European Heart Rhythm Association of the ESC and the Association of Cardiovascular Nursing & Allied Professions of the ESC, endorsed by the Association for European Paediatric and Congenital Cardiology.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Guideline
- 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
- Inactivation of CaV1 and CaV2 channels.The Journal of general physiology · 2025Review
- Synaptic plasticity deficits in a mouse model of Timothy syndrome: LTP saturation and its pharmacological rescue by nifedipine.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Article
- Voltage-gated calcium channels in genetic epilepsies.Journal of neurochemistry · 2024Review
- A novel computational model of swine ventricular myocyte reveals new insights into disease mechanisms and therapeutic approaches in Timothy Syndrome.Scientific reports · 2024Article
- Transmural APD heterogeneity determines ventricular arrhythmogenesis in LQT8 syndrome: Insights from Bidomain computational modeling.PloS one · 2024Article
- Examining Mechanisms for Voltage-Sensitive Calcium Channel-Mediated Secretion Events in Bone Cells.Calcified tissue international · 2023Review
- CACNA1C-Related Channelopathies.Handbook of experimental pharmacology · 2023Review
- Disruption of mitochondrial and lysosomal functions by humanFrontiers in molecular neuroscience · 2023Article
- Towards Zebrafish Models of CNS Channelopathies.International journal of molecular sciences · 2022Review
- Increased CaScientific reports · 2022Article
- CaV1.2 channelopathic mutations evoke diverse pathophysiological mechanisms.The Journal of general physiology · 2022Article
- Genetic determinants of syndactyly: perspectives on pathogenesis and diagnosis.Orphanet journal of rare diseases · 2022Review
- Calcium released by osteoclastic resorption stimulates autocrine/paracrine activities in local osteogenic cells to promote coupled bone formation.American journal of physiology. Cell physiology · 2022Article
- Comparison of Electrocardiogram and QT Interval between Viral Hepatitis Cirrhosis and Alcoholic Cirrhosis.Cardiology research and practice · 2022Article
- Novel CACNA1C R511Q mutation, located in domain Ⅰ-Ⅱ linker, causes non-syndromic type-8 long QT syndrome.PloS one · 2022Article
- A Review of Genetic and Physiological Disease Mechanisms Associated With Cav1 Channels: Implications for Incomplete Congenital Stationary Night Blindness Treatment.Frontiers in genetics · 2021Article
- Involvement of Calcium-Dependent Pathway and β Subunit-Interaction in Neuronal Migration and Callosal Projection Deficits Caused by the Cav1.2 I1166T Mutation in Developing Mouse Neocortex.Frontiers in neuroscience · 2021Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 1 country.
Funding
Abstract
backgroundTimothy syndrome (TS) is a rare multisystem genetic disorder characterized by a myriad of abnormalities, including QT prolongation, syndactyly, and neurologic symptoms. The predominant genetic causes are recurrent de novo missense mutations in exon 8/8A of the CACNA1C-encoded L-type calcium channel; however, some cases remain genetically elusive.
objectiveThe purpose of this study was to identify the genetic cause of TS in a patient who did not harbor a CACNA1C mutation in exon 8/A, and was negative for all other plausible genetic substrates.
methodsDiagnostic exome sequencing was used to identify the genetic substrate responsible for our case of TS. The identified mutation was characterized using whole-cell patch-clamp technique, and the results of these analyses were modeled using a modified Luo-Rudy dynamic model to determine the effects on the cardiac action potential.
resultsWhole exome sequencing revealed a novel CACNA1C mutation, p.Ile1166Thr, in a young male with diagnosed TS. Functional electrophysiologic analysis identified a novel mechanism of TS-mediated disease, with an overall loss of current density and a gain-of-function shift in activation, leading to an increased window current. Modeling studies of this variant predicted prolongation of the action potential as well as the development of spontaneous early afterdepolarizations.
conclusionThrough expanded whole exome sequencing, we identified a novel genetic substrate for TS, p.Ile1166Thr-CACNA1C. Electrophysiologic experiments combined with modeling studies have identified a novel TS mechanism through increased window current. Therefore, expanded genetic testing in cases of TS to the entire CACNA1C coding region, if initial targeted testing is negative, may be warranted.
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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.