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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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“2 (G406R) gives rise to Timothy syndrome (TS), an ASD that is also associated with severe cardiac symptoms including action potential prolongation and life-threatening arrhythmia (Splawski et al., 2004).”
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“2 α1-subunit (CACNA1C) variants G402S and G406R that affect the corresponding amino acid residue and cause Timothy syndrome, a multisystem disorder also associated with autism [7, 80, 81, 96].”
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“In support of such a notion, mechanisms involving alterations in metal ion transport have been implicated in Timothy syndrome, which results from a de novo missense mutation in a calcium channel gene in all affected tissues and is characterized by multiorgan dysfunction, cognitive abnormalities, and autism [34].”
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Ahnak, a new player in β-adrenergic regulation of the cardiac L-type Ca2+ channel
Haase, H. (2006) · Cardiovascular Research · doi:10.1016/j.cardiores.2006.09.001 · Cited by 67
Ca2+ current facilitation is CaMKII-dependent and has arrhythmogenic consequences
Bers, D. M., & Morotti, S. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00144 · Cited by 67
“For example, impaired VDI has been observed in Timothy syndrome (Splawski et al., 2004, 2005; Brunet et al., 2009), an inherited disease characterized by severe ventricular arrhythmias and sudden cardiac death.”
BackgroundPharmacogenetics of Adverse Drug Reactions
Osanlou, O., Pirmohamed, M., & Daly, A. K. (2018) · Advances in pharmacology · doi:10.1016/bs.apha.2018.03.002 · Cited by 69
Blazeski, A., Zhu, R., Hunter, D. W., Weinberg, S. H., Zambidis, E. T., & Tung, L. (2012) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2012.07.013 · Cited by 66
“This results in maintained inward Ca2þ currents due to loss of voltage-dependent Ca2þ channel inactivation (Splawski et al., 2004).”
BackgroundPhysiological genomics identifies genetic modifiers of long QT syndrome type 2 severity
Chai, S., Wan, X., Ramirez‐Navarro, A., Tesar, P. J., Kaufman, E. S., Ficker, E. K., George, A. L., & Deschênes, I. (2018) · Journal of Clinical Investigation · doi:10.1172/jci94996 · Cited by 70
“And while the seminal report of Splawski et al. (41) originally reported and linked CACNA1C mutations to Timothy syndrome Generation of patient-specific iPSCs .”
Autism spectrum disorder: prospects for treatment using gene therapy
Benger, M., Kinali, M., & Mazarakis, N. D. (2018) · Molecular Autism · doi:10.1186/s13229-018-0222-8 · Cited by 67
Developmental Activation of Calmodulin-Dependent Facilitation of Cerebellar P-Type Ca2+Current
Chaudhuri, D., Alseikhan, B. A., Chang, S. Y., Soong, T. W., & Yue, D. T. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2253-05.2005 · Cited by 66
“4E) (Welling et al., 1997; Regan et al., 2000; Splawski et al., 2004; Fan et al., 2005).”
Induced pluripotent stem cell–derived cardiomyocytes in studies of inherited arrhythmias
Priori, S. G., Napolitano, C., Pasquale, E. D., & Condorelli, G. (2013) · Journal of Clinical Investigation · doi:10.1172/jci62838 · Cited by 66
Self-citationGhaleb, Y. E., Schneeberger, P. E., Fernández‐Quintero, M. L., Geisler, S. M., Pelizzari, S., Polstra, A. M., van Hagen, J. M., Denecke, J., Campiglio, M., Liedl, K. R., et al. (2021) · Brain · doi:10.1093/brain/awab101 · Cited by 65
Clínica y genética en el síndrome de QT largo
Medeiros‐Domingo, A., Iturralde-Torres, P., & Ackerman, M. J. (2007) · Revista Española de Cardiología · doi:10.1157/13108280 · Cited by 67
Molecular Basis for Zinc Transporter 1 Action as an Endogenous Inhibitor of L-type Calcium Channels
Levy, S., Beharier, O., Etzion, Y., Mor, M., Buzaglo, L., Shaltiel, L., Gheber, L. A., Kahn, J., Muslin, A. J., Katz, A., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.058842 · Cited by 65
Disruption of the IS6-AID Linker Affects Voltage-gated Calcium Channel Inactivation and Facilitation
Findeisen, F., & Minor, D. L. (2009) · The Journal of General Physiology · doi:10.1085/jgp.200810143 · Cited by 66
“…VDI cause a multisystem disorder involving lethal heart arrhythmias, cognitive abnormalities, and immune defi ciencies, known as Timothy syndrome ( Splawski et al., 2004, 2005 ), provides further evidence for the importance of IS6 in channel gating and a compelling example of the physiological…”
BackgroundAlternative Splicing of L-type CaV1.2 Calcium Channels: Implications in Cardiovascular Diseases
Hu, Z., Liang, M. C., & Soong, T. W. (2017) · Genes · doi:10.3390/genes8120344 · Cited by 66
“Exon 8a, which is upstream of exon 8 in genomic sequence and known to be predominantly expressed in cardiac muscle [41], is labelled as exon 8 by the authors of the TS articles [31].”
BackgroundMutually exclusive alternative splicing of pre‐mRNAs
Jin, Y., Dong, H., Shi, Y., & Bian, L. (2018) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1468 · Cited by 69
“…indicate that the genes containing MXEs such as Drosophila neurexin IV and mammalian Mef2D undergo differential alternative splicing among different organisms and developmental stages (Graveley et al., 2011; Hatje & Kollmar, 2013; Sebastian et al., 2013; Stork et al., 2009; Wang et al., 2008).”
BackgroundL-type voltage-gated Ca 2+ channel Ca V 1.2 regulates chondrogenesis during limb development
Atsuta, Y., Tomizawa, R. R., Levin, M. G., & Tabin, C. J. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1908981116 · Cited by 65
“A missense mutation of Cacna1c (G406R), which is constitutively activated, and hence inappropriately increases intracellular Ca concentration, causes limb malformation in Timothy syndrome patients (23), and limb-specific overexpression of the G406R mutant in mice resulted in increase of bone mass in the limbs (38).”
BackgroundGenerating Human Neurons In Vitro and Using Them to Understand Neuropsychiatric Disease
Pașca, S. P., Panagiotakos, G., & Dolmetsch, R. E. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-062012-170328 · Cited by 68
“Timothy syndrome (TS) is caused by a point mutation in the voltage-gated calcium channel encoded by the CACNA1C gene and is one of the most penetrant forms of autism spectrum disorders (Splawski et al. 2004).”
BackgroundLong QT syndrome: beyond the causal mutation
Amin, A. S., Pinto, Y. M., & Wilde, A. A. M. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.254920 · Cited by 65
Monogenic mouse models of social dysfunction: Implications for autism
Oddi, D., Crusio, W. E., D'Amato, F. R., & Pietropaolo, S. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.01.002 · Cited by 66
Calcium Signaling in the Islets
Islam, M. S. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-90-481-3271-3_11 · Cited by 63
“hypoglycemia [72].”
Emerging evidence for specific neuronal functions of auxiliary calcium channel α2δ subunits
Geisler, S. M., Schöpf, C. L., & Obermair, G. J. (2015) · General Physiology and Biophysics · doi:10.4149/gpb_2014037 · Cited by 67
Calcium Channel Mutations in Cardiac Arrhythmia Syndromes
Betzenhauser, M. J., Pitt, G. S., & Antzelevitch, C. N. (2015) · Current Molecular Pharmacology · doi:10.2174/1874467208666150518114857 · Cited by 64
Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome
Panagiotakos, G., Haveles, C. S., Arjun, A., Petrova, R., Rana, A., Portmann, T., Pașca, S. P., Palmer, T. D., & Dolmetsch, R. E. (2019) · eLife · doi:10.7554/elife.51037 · Cited by 65
“2 (Splawski et al., 2004).”
BackgroundInfluentialLi, B., Suutari, B. S., Sun, S. D., Luo, Z.-Y., Wei, C., Chenouard, N., Mandelberg, N. J., Zhang, G., Wamsley, B., Tian, G., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.013 · Cited by 62
Griswold, A. J., Dueker, N., Booven, D. V., Rantus, J. A., Jaworski, J. M., Slifer, S. H., Schmidt, M. A., Hulme, W. F., Konidari, I., Whitehead, P. L., et al. (2015) · Molecular Autism · doi:10.1186/s13229-015-0034-z · Cited by 66
“CACNA2D1 regulates influx of calcium ions into the cell upon membrane polarization and Mutations in a related gene (CACNA1C) are known to cause Timothy syndrome which includes neurological and developmental deficits and often autism symptoms [85].”
BackgroundAuxiliary Ca2+ channel subunits: lessons learned from muscle
Obermair, G. J., Tuluc, P., & Flucher, B. E. (2008) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2008.01.008 · Cited by 63
Wilde, A. A. M., Semsarian, C., Márquez, M. F., Shamloo, A. S., Ackerman, M. J., Ashley, E. A., Sternick, E. B., Barajas-Martínez, H., Behr, E. R., Bezzina, C. R., et al. (2022) · Journal of Arrhythmia · doi:10.1002/joa3.12717 · Cited by 67
Self-citationTiming in Cellular Ca2+ Signaling
Boulware, M. J., & Marchant, J. S. (2008) · Current Biology · doi:10.1016/j.cub.2008.07.018 · Cited by 63
Clinical Outcomes and Modes of Death in Timothy Syndrome
Dufendach, K., Timothy, K. W., Ackerman, M. J., Blevins, B., Pflaumer, A., Etheridge, S. P., Perry, J. C., Blom, N. A., Temple, J., Chowdhury, D., et al. (2017) · JACC. Clinical electrophysiology · doi:10.1016/j.jacep.2017.08.007 · Cited by 62
Self-citationBrain Organoids as Tools for Modeling Human Neurodevelopmental Disorders
Adams, J. W., Cugola, F. R., & Muotri, A. R. (2019) · Physiology · doi:10.1152/physiol.00005.2019 · Cited by 68
Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine
Gao, S., Yao, X. Y., Chen, J., Huang, G., Fan, X., Xue, L., Li, Z., Wu, T., Zheng, Y., Huang, J., et al. (2023) · Cell · doi:10.1016/j.cell.2023.10.007 · Cited by 61
Hyperinsulinism in Developmental Syndromes
Kapoor, R. R., James, C. T., & Hussain, K. (2009) · Endocrine development · doi:10.1159/000207480 · Cited by 61
Abiria, S. A., & Colbran, R. J. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06436.x · Cited by 61
“2 LTCCs by CaMKII is implicated in Timothy Syndrome, a multi-organ human genetic disorder whose symptoms include mental retardation and cardiac disease (Splawski et al. 2004, 2005; Erxleben et al. 2006; Thiel et al. 2008).”
BackgroundThe Role of the GX9GX3G Motif in the Gating of High Voltage-activated Ca2+ Channels
Raybaud, A., Dodier, Y., Bissonnette, P., Simoes, M., Bichet, D. G., Sauvé, R., & Parent, L. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m607405200 · Cited by 61
Human heart disease: lessons from human pluripotent stem cell-derived cardiomyocytes
Giacomelli, E., Mummery, C. L., & Bellin, M. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2546-5 · Cited by 60
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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