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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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“Alseikhan et al. (2002) showed the effects of CaM1234 expression, which inhibits CDI and produces dramatic AP prolongation, whereas Splawski et al. (2004) showed the effects of the G406R mutation that removes VDI and is linked to the Timothy syndrome.”
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“Children with this disorder have small and misplaced teeth which, due to enamel hypoplasia, are prone to dental cavities and often require removal (Splawski et al., 2004).”
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“Similarly, gain of function of mutations in the CA CNA1C gene which encodes the L- Type Ca channel Cav 1.2 leads to immunodeficiency and autism in addition to prolonged QT interval and is termed Timothy syndrome or LQT8 (Splawski et al., 2004).”
BackgroundInfluentialQT Prolongation and Malignant Arrhythmia: How Serious a Problem?
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“Integrating the data from TS [2], the meta-analysis of psychiatric disorders [22], and functional studies on auxiliary b-subunits, we propose that inappropriate function of different components of the voltage-gated calcium channel complex can result in or may contribute to autism spectrum disorder.”
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“2, is associated with multiple developmental defects including fusion of the digits of the hands or feet (syndactyly) and craniofacial defects in humans (Splawski et al., 2004; Splawski et al., 2005).”
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The E646D-ATP13A4 Mutation Associated with Autism Reveals a Defect in Calcium Regulation
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“2 Rare [26] CAV3 (LQT9) 3p25 Caveolin 3 Rare [27] SCN4B (LQT10) 11q23.”
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“Forexample, a gain-of-functionmissense mutation in CACNA1C, a gene encoding an L-type calcium channel, causes Timothy Syndrome (Splawski et al. 2004).”
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“Another link between L-type Ca 2 + channels and cardiac arrhythmias was established by the study of patients affected by Timothy syndrome (Splawski et al. 2004).”
BackgroundGenetics of ion-channel disorders
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Self-citationNeuro-Cardio Mechanisms in Huntington’s Disease and Other Neurodegenerative Disorders
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“Similar to HD, patients suffer from a prolonged QT interval and structural heart defects in addition to neurodevelopmental delay, seizures, and autism-spectrum disorder symptoms (Splawski et al., 2004).”
Backgroundα1ACT Is Essential for Survival and Early Cerebellar Programming in a Critical Neonatal Window
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“The CACNA1C channel consists of four homologous domains (DI–DIV), each comprised of six transmembrane segments, cytoplasmic segments, and transmembrane linker segments [1, 22].”
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“2subunit has been identified in humans (Splawski et al. 2004).”
Concise Review: Cardiac Disease Modeling Using Induced Pluripotent Stem Cells
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“Recently, several studies revealed that SNPs in this gene were associated with psychiatric disorders such as bipolar disorder, autism, and schizophrenia (Splawski et al. 2004, 2005; Ferreira et al. 2008; Sklar et al. 2008; Moskvina et al. 2009).”
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Three-dimensional microengineered models of human cardiac diseases
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Sudden infant death syndrome: Do ion channels play a role?
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Zhang, Z., Wang, X., Park, S. S., Song, H., & Ming, G. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.12.015 · Cited by 49
“Cortical organoids derived from patients with Timothy syndrome showed hypersynchronous network calcium dynamics, which were further exacerbated in cortical-subpallial assem-bloids (83), consistent with clinical features of frequent recurrent seizures in patients with Timothy syndrome (93).”
Robert, V., Triffaux, E., Paulet, P.-E., Guéry, J., Pelletier, L., & Savignac, M. (2013) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2013.10.038 · Cited by 47
“2, which is responsible for a gain of function of the channel and display, among other disorders, increased susceptibility to recurrent infections.(15,16) Correct cell functions depend on a tight regulation of intracellular Ca(21) levels, and both loss and gain of function of Cav1 were shown to induce alterations in c…”
Cardiac Ion Channelopathies and the Sudden Infant Death Syndrome
Wilders, R. (2012) · ISRN Cardiology · doi:10.5402/2012/846171 · Cited by 48
“As a result, LQT8 is not only characterized by QT prolongation and other cardiac symptoms, but also by syndactyly of fingers and toes, intermittent hypoglycemia, immune deficiency, cognitive abnormalities, and autism [108, 111].”
BackgroundCounteracting Protein Kinase Activity in the Heart: The Multiple Roles of Protein Phosphatases
Weber, S., Meyer-Roxlau, S., Wagner, M., Dobrev, D., & El‐Armouche, A. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00270 · Cited by 50
“2 interactions might be a versatile drug targeting in the future (Splawski et al., 2004; Tang et al., 2008; Domes et al., 2011; Hong et al., 2012; Tajada et al., 2013).”
BackgroundBiamino, E., Gregorio, E. D., Belligni, E. F., Keller, R., Riberi, E., Gandione, M., Calcia, A., Mancini, C., Giorgio, E., Cavalieri, S., et al. (2015) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32406 · Cited by 49
“Noteworthy, calcium channels and regulators of calcium homeostasis have been repeatedly implicated in ASD, ID, and schizophrenia [Splawski et al., 2004; Endele et al., 2010; Ripke et al., 2013; De Rubeis et al., 2014; Purcell et al., 2014].”
BackgroundMizoguchi, Y., & Monji, A. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00069 · Cited by 48
“3 channels are a major class of L-type VGCCs which constitute an important calcium entry pathway implicated in the regulation of spine morphology and then contribute to the rhythmicity of brain (Stanika et al., 2016).”
BackgroundBozarth, X., Dines, J. N., Cong, Q., Mirzaa, G., Foss, K., Merritt, J. L., Thies, J. M., Mefford, H. C., & Novotny, E. J. (2018) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.40657 · Cited by 48
“2018;176A:2733–2739. wileyonlinelibrary.com/journal/ajmga © 2018 Wiley Periodicals, Inc. 2733 Napolitano, Splawski, Timothy, Bloise, & Priori, 1993; Reichenbach, Meister, & Theile, 1992; Splawski et al., 2004).”
BackgroundInfluentialFreire, P. P., Fernández, G. J., Cury, S. S., de Moraes, D., Oliveira, J. S., de Oliveira, G., Dal‐Pai‐Silva, M., Reis, P. P., & Carvalho, R. F. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081962 · Cited by 45
Hopp, S. C. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24585 · Cited by 50
“2, lead to heart arrhythmias and structural cardiac defects, immune system dysfunction, neurodevelopmental difficulties such as ASD, and physical malformations such as syndactyly (Dixon, Cheng, Mercado, & Santana, 2012; Liao & Soong, 2010; Splawski et al., 2004).”
BackgroundIon Channels Involvement in Neurodevelopmental Disorders
D’Adamo, M. C., Liantonio, A., Conte, E., Pessia, M., & Imbrici, P. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.05.032 · Cited by 47
Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms
Uzun, E. D. G., Sciarra, L. N., Maguire, A. M., Pescosolido, M. F., van Dyck, L. I., & Morrow, E. M. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0363-9 · Cited by 45
Faßl, J., High, K. M., Stephenson, E. R., Yarotskyy, V., & Elmslie, K. S. (2010) · The Journal of Clinical Pharmacology · doi:10.1177/0091270010373098 · Cited by 46
“PHArMACODYnAMICS 723 mutation highlights the importance of this inactivation mechanism in maintaining normal cardiac rhythm.(29) Thus, it is critical that the effect of propofol on voltage-dependent inactivation be investigated.”
BackgroundCasanova, M., & Casanova, M. F. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00397 · Cited by 48
“One of the clearest examples lies in the condition known as Timothy Syndrome (TS), which exhibits at least 60% comorbidity rate with autism, the highest penetrance for syndromic autism to date (Splawski et al., 2004).”
BackgroundCalorio, C., Gavello, D., Guarina, L., Salio, C., Sassoé‐Pognetto, M., Riganti, C., Bianchi, F. T., Hofer, N. T., Tuluc, P., Obermair, G. J., et al. (2019) · The Journal of Physiology · doi:10.1113/jp277487 · Cited by 46
“Timothy syndrome (TS) is a rare multiorgan channelopathy characterized by cardiac arrhythmias, long QTs, immune deficiencies and autism (Splawski et al. 2004, 2005).”
BackgroundInfluentialGenetic Mosaicism in Calmodulinopathy
Wren, L. M., Jiménez‐Jáimez, J., Alghamdi, S. A. A., Al-Aama, J. Y., Bdeir, A., Al‐Hassnan, Z. N., Kuan, J. L., Foo, R., Potet, F., Johnson, C. N., et al. (2019) · Circulation Genomic and Precision Medicine · doi:10.1161/circgen.119.002581 · Cited by 46
Self-citationAlternative splicing of voltage-gated calcium channels: from molecular biology to disease
Liao, P. H., Zhang, H. Y., & Soong, T. W. (2009) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-009-0635-5 · Cited by 46
“channelopathy is the role of alternative splicing in modulating severity of disorder associated with Timothy syndrome [50, 51 ].”
BackgroundCalcium signaling phenomena in heart diseases: a perspective
Chakraborti, S., Das, S. K., Kar, P., Ghosh, B., Samanta, K., Kolley, S., Ghosh, S., Roy, S., & Chakraborti, T. (2006) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-006-9355-8 · Cited by 46
“Ceramide has been shown to mediate some biological effects of IL-1b and TNF-a, two primary proinflammatory cytokines [177] and prostaglandin E2 [12, 17].”
BackgroundKuryshev, Y. A., Wang, L., Wible, B. A., Wan, X., & Ficker, E. K. (2006) · Molecular Pharmacology · doi:10.1124/mol.105.019281 · Cited by 46
“2 (Splawski et al., 2004, 2005).”
Harrison, P. J., Husain, S. M., Lee, H., Angeles, A. D. L., Colbourne, L., Mould, A. W., Hall, N., Haerty, W., & Tunbridge, E. M. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109262 · Cited by 45
Ranolazine Safely Decreases Ventricular and Atrial Fibrillation in Timothy Syndrome (LQT8)
Shah, D. P., Báez-Escudero, J. L., Weisberg, I., Beshai, J. F., & Burke, M. C. (2010) · Pacing and Clinical Electrophysiology · doi:10.1111/j.1540-8159.2010.02913.x · Cited by 45
CaBP1 Regulates Voltage-dependent Inactivation and Activation of CaV1.2 (L-type) Calcium Channels
Oz, S., Tsemakhovich, V., Christel, C. J., Lee, A., & Dascal, N. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.198424 · Cited by 48
Biophysical Properties of 9 KCNQ1 Mutations Associated With Long-QT Syndrome
Yang, T., Chung, S., Zhang, W., Mullins, J. G. L., McCulley, C. H., Crawford, J., MacCormick, J. M., Eddy, C.-A., Shelling, A. N., French, J. K., et al. (2009) · Circulation Arrhythmia and Electrophysiology · doi:10.1161/circep.109.850149 · Cited by 44
Calcium Channel CaVα1 Splice Isoforms - Tissue Specificity and Drug Action
Lipscombe, D., & Andrade, A. (2015) · Current Molecular Pharmacology · doi:10.2174/1874467208666150507103215 · Cited by 44
“Interestingly, rare mutations in either one of a pair of alternatively spliced exons in CACNA1C (e8 or e8a) underlie the devastating Timothy Syndromes characterized by severe multi-organ disorders including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypog…”
BackgroundCao, C., Ren, Y., Barnett, A. S., Mirando, A. J., Rouse, D. C., Mun, S. H., Park‐Min, K., McNulty, A. L., Guilak, F., Karner, C. M., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.95512 · Cited by 45
Dynamic L-type CaV1.2 channel trafficking facilitates CaV1.2 clustering and cooperative gating
Ghosh, D., Nieves‐Cintrón, M., Tajada, S., Brust‐Mascher, I., Horne, M. C., Hell, J. W., Dixon, R. E., Santana, L. F., & Navedo, M. F. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.06.013 · Cited by 46
Human Brain Organoid Models of Developmental Epilepsies
Nieto‐Estévez, V., & Hsieh, J. (2020) · Epiliepsy currents/Epilepsy currents · doi:10.1177/1535759720949254 · Cited by 44
Pharmacological approach to the treatment of long and short QT syndromes
Patel, C., & Antzelevitch, C. N. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.02.001 · Cited by 45
“2, leads to multi-organ disease including prolongation of QT interval, immunodeficiency and autism (Splawski et al., 2004).”
BackgroundYamada, M., Ohta, K., Niwa, A., Tsujino, N., Nakada, T., & Hirose, M. (2008) · The Journal of Membrane Biology · doi:10.1007/s00232-008-9113-9 · Cited by 45
“The former arise from the reduction of net outward currents during phase 2 repolarization which occurs in LQT syndromes (Brugada & Wellens, 1985; Antzelevitch & Shimizu, 2002; Splawski et al., 2004).”
InfluentialChang, J., Hazelett, D. J., Stewart, J. A., & Morton, D. B. (2013) · Brain Research · doi:10.1016/j.brainres.2013.11.019 · Cited by 44
“Similarly, mutations in exon 8a or exon8 of cacna1c determine the symptoms in Type I and Type II Timothy Syndrome (Splawski et al, 2004), as well as the association between Cacna1a (CaV2.”
BackgroundGentile, S., Martin, N. P., Scappini, E., Williams, J. G., Erxleben, C. F. J., & Armstrong, D. L. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802250105 · Cited by 43
Cosgrove, D., Mothersill, O., Kendall, K., Konte, B., Harold, D., Giegling, I., Hartmann, A., Richards, A., Mantripragada, K., Owen, M., et al. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2017.123 · Cited by 37
Perioperative management of patients with congenital or acquired disorders of the QT interval
O’Hare, M., Maldonado, Y., Munro, J., Ackerman, M. J., Ramakrishna, H., & Sorajja, D. (2018) · British Journal of Anaesthesia · doi:10.1016/j.bja.2017.12.040 · Cited by 48
Sleep as a translationally-relevant endpoint in studies of autism spectrum disorder (ASD)
Missig, G., McDougle, C. J., & Carlezon, W. A. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0409-5 · Cited by 49
L-type calcium channel mutations in Japanese patients with inherited arrhythmias.
Fukuyama, M., Ohno, S., Wang, Q., Kimura, H., Makiyama, T., Itoh, H., Ito, M., & Horie, M. (2013) · Circulation Journal · doi:10.1253/circj.cj-12-1457 · Cited by 41
Napolitano, C., Bloise, R., & Priori, S. G. (2006) · Journal of Cardiovascular Medicine · doi:10.2459/01.jcm.0000219317.12504.5f · Cited by 44
Self-citationThe Congenital Long QT Syndrome and Implications for Young Athletes
Kapetanopoulos, A., Kluger, J., Maron, B. J., & Thompson, P. D. (2006) · Medicine & Science in Sports & Exercise · doi:10.1249/01.mss.0000218130.41133.cc · Cited by 44
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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