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CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism
Open accessAbstract
Ca(V)1.2, the cardiac L-type calcium channel, is important for excitation and contraction of the heart. Its role in other tissues is unclear. Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. In every case, Timothy syndrome results from the identical, de novo Ca(V)1.2 missense mutation G406R. Ca(V)1.2 is expressed in all affected tissues. Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca(2+) overload in multiple cell types. In the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in this disorder. These discoveries establish the importance of Ca(V)1.2 in human physiology and development and implicate Ca(2+) signaling in autism.
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“Further, there is clear evidence from Timothy syndrome (TS), a rare genetic disorder arising from mutation of either CACNA1C or CACNB2, that improper function of a Ca2+ channel can engender ASD with a penetrance as high as 60-80% (Breitenkamp et al., 2014; Splawski et al., 2005; Splawski et al., 2004).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Splawski et al., 2004
In the citing paper
“Over 60% of TS patients also fulfill the criteria for an autism spectrum disorder (ASD)1 making TS one of the most penetrant monogenic forms of autism.”
From Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome (2011) · cites this paper as [1]
In the citing paper
“Timothy syndrome is caused by a missense mutation in the L-type calcium channel Cav1.2 that is associated with developmental delay and autism 1.”
From Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome (2011) · cites this paper as [1]
In the citing paper
“TS is caused by a point mutation in an alternatively spliced exon of CACNA1C, the gene that encodes the α1 subunit of Cav1.21.”
From Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome (2011) · cites this paper as [1]
In the citing paper
“This mutation leads to decreased calcium- and voltage-dependent inactivation of the channel1,9.”
From Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome (2011) · cites this paper as [1]
In the citing paper
“For example, mutations in the voltage-gated L-type calcium channels that flux calcium to initiate activity-dependent gene transcription are associated with Timothy syndrome, which is characterized by impairments in cardiac and immune function and has a significant association with ASD phenotypes31.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [31]
In the citing paper
“Studies in mice indicate that this missense mutation leads to increased Ca2+ currents and loss of voltage-dependent channel inactivation31,77.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [31]
In the citing paper
“Timothy syndrome, a disorder characterized by cardiac arrhythmia, congenital heart disease, immune deficiency, intermittent hypoglycaemia, global development delay and ASD, is caused by a missense mutation in CACNA1C31.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [31]
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“They could also be classified as “Timothy Syndrome- like” mutations because they are very similar to the Cav1.”
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“Missense mutations of this gene cause a syndromic form of HH, Timothy syndrome, which is characterized with multi-system disorders including lethal cardiac arrhythmias, congenital heart defects, syndactyly, immune deficiency, intermittent HH, intellectual disability, autism, and autistic spectrum disorders [48].”
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“2 isoform of the Ca channel (associated with Timothy syndrome) delays AP repolarization, thus explaining the associated arrhythmia (Splawski et al., 2004).”
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BackgroundMethodState-dependent signaling by Cav1.2 regulates hair follicle stem cell function
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“TS patients are born bald and display a severe delay in the onset of the first postnatal hair growth (Splawski et al. 2004).”
BackgroundInfluentialMolecular alteration of Cav1.2 calcium channel in chronic myocardial infarction
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“Mutations within an alternatively spliced exon of Cav1.2, representing only a small population (23%) of total Cav1.2 channels in heart, could cause lethal ventricular arrhythmia [ 18 ].”
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“(51) measured the effects of a Timothy syndrome mutation on the inactivation of the L-type Ca2+ channels and modelled their effects on cardiomyocyte action potentials.”
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“2 encoded by CACN1C gene, leading to LQTS type 8, and additional impairments such as webbing of fingers and toes, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism [252].”
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“Birey et al. demonstrate the recapitulation of this developmental phenomenon, and further apply it to a model of Timothy syndrome (TS), a neurodevelopmental disorder which impacts multiple body systems (Splawski et al., 2004).”
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“Electrophysiological studies of G406R in exon 8A and G406R/G402S in exon8 showed almost complete loss of inactivation of CaV1.”
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“…mutations have been shown to have dominant negative effects, including changing the gating properties of the channel pore or binding other subunits and inhibiting their localization to the cell membrane (Plaster et al., 2001; Splawski et al., 2004, 2005; Stump, Gong, Packer, & Zhou, 2012).”
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“cardiac cells [1,2] resulting in cardiac arrhythmias.”
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“2 channel of TS mutations (G406R, G402S) is larger by causing almost complete loss of VDI.(3) Analysis of TS Cav1.”
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“This mutation, p.Gly406Arg, delays calcium channel inactivation which results in a prolonged calcium current influx into the cells, delaying repolarization and making the heart more susceptible to ventricular arrhythmias [Splawski et al., 2004].”
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Long QT syndrome – Bench to bedside
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Precision Medicine Approaches to Cardiac Arrhythmias
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Calcium channels as therapeutic targets
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The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment
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L-type Ca2+ channel mutations and T-wave alternans: a model study
Zhu, Z. I., & Clancy, C. E. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00476.2007 · Cited by 28
Soda, T., Pasqua, T., Sarro, G. D., & Moccia, F. D. (2024) · Biomedicines · doi:10.3390/biomedicines12102387 · Cited by 28
“This mutation exerts a gain-of-function effect that shifts the threshold of activation towards more negative potentials and removes the voltage-dependent inactivation of L-type Ca 2+ currents, thereby leading to intracellular Ca 2+ overload [242].”
BackgroundInfluentialSchwartz, P. J., & Crotti, L. (2025) · New England Journal of Medicine · doi:10.1056/nejmra2400853 · Cited by 27
Self-citationExpansion of the mutually exclusive spliced exome in Drosophila
Hatje, K., & Kollmar, M. (2013) · Nature Communications · doi:10.1038/ncomms3460 · Cited by 26
Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome
Song, L., Park, S.-H. E., Isseroff, Y., Morikawa, K., & Yazawa, M. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.05.028 · Cited by 28
“2 channel are associatedwith Timothy syndrome (TS), amultisystemdisorder that features long-QT syndrome and syndactyly (Boczek et al., 2015; Hennessey et al., 2014; Papineau and Wilson, 2014; Splawski et al., 2004).”
InfluentialProteolytic processing of the L-type Ca2+ channel alpha11.2 subunit in neurons
Buonarati, O. R., Henderson, P. B., Murphy, G. G., Horne, M. C., & Hell, J. W. (2017) · F1000Research · doi:10.12688/f1000research.11808.1 · Cited by 27
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Absence of the Inhibitory G-Protein Gα i2 Predisposes to Ventricular Cardiac Arrhythmia
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“In humans, alterations in Cav1 abundance or function result in a variety of diseases, including hypertension [4], Timothy Syndrome [5], and congenital stationary night blindness [6].”
BackgroundSadrieh, A., Mann, S. A., Subbiah, R., Domanski, L., Taylor, J. A., Vandenberg, J., & Hill, A. (2013) · Journal of Physiology · doi:10.1113/jphysiol.2013.251710 · Cited by 21
“2007), whereas gain of function mutations in calcium channel subunits lead to increased QT duration (Splawski et al. 2004).”
BackgroundThe Human Model: Changing Focus on Autism Research
Muotri, A. R. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.03.012 · Cited by 27
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Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations
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“The predominant genetic cause of TS1, identified in 2004 [Splawski et al., 2004], was a recurrent, canonical “de novo” heterozygous missense mutation, p.Gly406Arg, in the alternatively spliced exon 8A in the CACNA1C gene, encoding for the main cardiac L-type calcium channel, Cav1.”
BackgroundInfluentialAbnormal Excitation-Contraction Coupling and Calcium Homeostasis in Myopathies and Cardiomyopathies
Schartner, V., Laporte, J., & Böhm, J. (2019) · Journal of Neuromuscular Diseases · doi:10.3233/jnd-180314 · Cited by 29
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Ion Channels and Transporters in Muscle Cell Differentiation
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Voltage‐gated calcium channels in genetic epilepsies
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Etiological Heterogeneity in Autism Spectrum Disorders
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“… Extremely rare 80% (4/5) ASD ID, ASD, cardiac abnormalities (long QT syndrome, malformations), hand/foot syndactyly, facial dysmorphism, seizures (Splawski et al., 2004) Cortical dysplasia-‐focal epilepsy syndrome (10 individuals reported) CNTNAP2…”
Gene-specific therapy for inherited arrhythmogenic diseases
Napolitano, C., Bloise, R., & Priori, S. G. (2005) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.08.003 · Cited by 26
Self-citationCardiac Ion Channel Safety Profiling on the IonWorks Quattro Automated Patch Clamp System
Cao, X., Lee, Y. T., Holmqvist, M., Lin, Y., Ni, Y., Mikhailov, D., Zhang, H., Hogan, C. J., Zhou, L., Lü, Q., et al. (2010) · Assay and Drug Development Technologies · doi:10.1089/adt.2010.0333 · Cited by 26
Isolation and Physiological Analysis of Mouse Cardiomyocytes
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“1 current, long QT interval and skeletal abnormalities (Andersen-Tawil’s syndrome) (LQT7; Plaster, et al., 2001); ii) mutation in the CACNA1C gene results in an increase in Cav1.”
BackgroundJalloul, A. H., Rogasevskaia, T. P., Szerencsei, R. T., & Schnetkamp, P. P. M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.728824 · Cited by 26
“Mutations in the CACNA1C gene that codes for the Cav1 channel are associated with Timothy syndrome, which is a multisystem disorder presented with enamel hypoplasia, small teeth, and several other physiological abnormalities in the heart and other organs (OMIM 601005) (3).”
BackgroundNapolitano, C., Bloise, R., & Priori, S. G. (2013) · Elsevier eBooks · doi:10.1016/b978-1-4557-2856-5.00095-9 · Cited by 27
Self-citationFindlay, I., Suzuki, S., Murakami, S., & Kurachi, Y. (2007) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2007.07.002 · Cited by 26
Metadata
- Authors
- Splawski, I., Timothy, K. W., Sharpe, L. M., Decher, N., Kumar, P., Bloise, R., Napolitano, C., Schwartz, P. J., Joseph, R. M., Condouris, K., Tager-Flusberg, H., Priori, S. G., Sanguinetti, M. C., & Keating, M. T.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Utah (US)
- Istituti Clinici Scientifici Maugeri (IT)
- University of Pavia (IT)
- Boston University (US)
- Corresponding author
- Splawski, Igor
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2004-10
- Volume
- 119
- Issue
- 1
- Pages
- 19-31
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2138773108
- Cited by
- 1,586
- References
- 61
- Citations by year
- 2026: 34 · 2025: 48 · 2024: 64 · 2023: 49 · 2022: 76 · 2021: 66 · 2020: 80 · 2019: 70 · 2018: 90 · 2017: 92 · 2016: 73 · 2015: 85 · 2014: 66 · 2013: 114 · 2012: 98
- FWCI
- 41.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- National Heart, Lung, and Blood Institute (HL46401, HL-52338, P50HL052338, T32HL007572)
- National Institute of Mental Health (MH66398, U54MH066398)
- National Institute on Deafness and Other Communication Disorders (DC03610)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Cav1.2, cardiac L-type calcium channel, Timothy syndrome, de novo missense variant, cardiac arrhythmias, autism spectrum disorder, multisystem disease, congenital heart disease, immunodeficiency, hypoglycemia, intracellular calcium overload, calcium signaling, channel inactivation
- MeSH terms
- Abnormalities, Multiple, Action Potentials, Animals, Arrhythmias, Cardiac, Autistic Disorder, Brain, Brain Chemistry, Calcium, Cell Membrane, Child, Female, Cricetinae, Heart, Humans, Infant, Newborn, Male, Neurons, Oocytes, Pedigree, Syndrome, Xenopus laevis, CHO Cells, Limb Deformities, Congenital, Calcium Signaling, Mutation, Missense, Calcium Channels, L-Type, Genetic Diseases, Inborn, Myocytes, Cardiac, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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