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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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“This mutation sharply reduces calcium channel inactivation, which may lead to heightened Ca2+ influx (Barrett & Tsien, 2008; Splawski et al., 2004).”
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“2 (Depil et al., 2011), which are known to lead to the Timothy syndrome, a channelopathy consisting of physical, neurological and developmental defects (Splawski et al., 2004).”
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“…also implicated in the severe neurodevelopmental disorder Timothy syndrome, in which a gain-of-function single nucleotide polymorphism (G406R) in exon 8/8A of CACNA1C results in a functional channel with disrupted inactivation and an extremely high penetrance of ASD (Splawski et al., 2004, 2005).”
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BackgroundInherited Arrhythmia Syndromes
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“Jervell and Lange-Nielsen syndrome and Timothy syndrome (LQTS8) represent two of the more malignant subtypes [11,12].”
BackgroundInactivation of CaV1 and CaV2 channels
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“In an analogous manner in Timothy syndrome the G406R mutation in CACN1C results in increased calcium current due to a loss of inactivation (Splawski et al., 2004).”
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“2 subunits and causes Timothy syndrome, a human disorder associated with fatal ventricular arrhythmias, syndactyly, immune deficiency and autism (Splawski et al., 2004).”
BackgroundMethodInfluentialGenetic Intersections of Language and Neuropsychiatric Conditions
Koomar, T., & Michaelson, J. J. (2020) · Current Psychiatry Reports · doi:10.1007/s11920-019-1123-z · Cited by 11
Shank promotes action potential repolarization by recruiting BK channels to calcium microdomains
Gao, L., Zhao, J., Ardiel, E., Hall, Q., Nurrish, S., & Kaplan, J. M. (2022) · eLife · doi:10.7554/elife.75140 · Cited by 10
Silva, A. L. T. E., Glaser, T., Griesi‐Oliveira, K., Corrêa-Velloso, J. C., Wang, J. Y. T., Campos, G. D. S., Ulrich, H., Balan, A., Zarrei, M., Higginbotham, E. J., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01997-9 · Cited by 11
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“The loss-offunction mutation in hERG identified in the current study might underlie the pathogenesis of her SCD. Patients with LQT2 are highly vulnerable to alterations in their physical and mental states that involve sympathetic surges [6].”
BackgroundInfluentialThe Genetics of Congestive Heart Failure
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Harnessing the Flow of Excitation
Frolov, R. V., & Weckström, M. (2015) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2015.11.001 · Cited by 12
Lin, K., Xu, G., Shi, L., Lu, W., Guan, L., Ouyang, H., Chen, K., Dang, Y., Zhou, L., & So, K. (2017) · Scientific Reports · doi:10.1038/s41598-017-07368-5 · Cited by 11
The Congenital Long QT Syndrome
Lazzara, R. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.11.048 · Cited by 10
Developmental convergence and divergence in human stem cell models of autism spectrum disorderPreprint
Gordon, A., Yoon, S., Bicks, L. K., Martín, J. M., Pintacuda, G., Arteaga, S., Wamsley, B., Guo, Q., Elahi, L. S., Dolmetsch, R. E., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.01.587492 · Cited by 10
Endoplasmic Reticulum Calcium Mediates Drosophila Wing Development
George, L. F., Follmer, M. L., Fontenoy, E., Moran, H. R., Brown, J., Ozekin, Y. H., & Bates, E. A. (2023) · Bioelectricity · doi:10.1089/bioe.2022.0036 · Cited by 9
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Splice-switching antisense oligonucleotides for pediatric neurological disorders
Zhang, X. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1412964 · Cited by 9
Depolarization induces calcium-dependent BMP4 release from mouse embryonic palate mesenchymal cells
Follmer, M. L., Isner, T. J., Ozekin, Y. H., Levitt, C. H., Burek, C. L., Benninger, R. K. P., & Bates, E. A. (2024) · Nature Communications · doi:10.1038/s41467-024-53642-2 · Cited by 9
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“…single nucleotide polymorphism (G406R) in exon 8/8A of CACNA1C causes TS, a rare multisystem condition characterized by congenital heart defects, immune dysregulation, neurodevelopmental impairments, and a high prevalence of ASD (Bauer et al., 2021; Splawski et al., 2005; Splawski et al., 2004).”
Neural network modelling of the influence of channelopathies on reflex visual attention
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“The canonical TS1 variant Gly406Arg results from a de novo CACNA1C mutation in exon 8A (20).”
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The role of trace elements thiamin e in autism and autistic spectrum disorder
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Smooth Muscle Phenotypic Diversity
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Buddell, T., & Quinn, C. C. (2021) · PubMed Central · doi:10.17912/micropub.biology.000378 · Cited by 9
“These mutations cause either a G402R, G402S or G406R mutation in the CACNA1C protein (Splawski et al., 2004; Bader et al., 2011).”
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Clinical Approach to Inborn Errors of Metabolism in Paediatrics
Saudubray, J., & García‐Cazorla, À. (2022) · Springer eBooks · doi:10.1007/978-3-662-63123-2_1 · Cited by 10
Kummer, S., Rinné, S., Seemann, G., Bachmann, N., Timothy, K. W., THORNTON, P. S., Pillekamp, F., Mayatepek, E., Bergmann, C., Meißner, T., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158097 · Cited by 9
“Besides further syndromic features like syndactyly, immune deficiency, cognitive abnormalities and autism, intermittent hypoglycemia of yet unproven origin was reported in 36% of patients [1].”
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Ghais, N. S., Zhang, Y., Grace, A. A., & Huang, C. L.-H. (2008) · Experimental Physiology · doi:10.1113/expphysiol.2008.044669 · Cited by 9
“All 8 hearts showed episodes of sVT lasting for more than 30 s with further perfusion with FPL for more than 10 min (C). refractory period, since alterations in these have been observed in previous long QT syndrome (LQTS) and hypokalaemic murine cardiac models and have been implicated in the re-entrant substrate respo…”
BackgroundNuevas perspectivas en el síndrome de QT largo
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CYFIP1 governs the development of cortical axons by modulating calcium availability
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“val; (3) the 3 mutations are not observed in ethnically matched healthy individuals; and (4) there is a clear genotype-phenotype”
BackgroundSelf-citation
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
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