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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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“syndrome, a multifaceted disease in which mutations that impair voltagedependent inactivation cause arrhythmia, developmental abnormalities, and autism spectrum disorder (51).”
BackgroundNeuronal regulation of pre-mRNA splicing by polypyrimidine tract binding proteins, PTBP1 and PTBP2
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“Exon 8A is also interesting as the site of human mutations causing Timothy syndrome (TS) (Splawski et al., 2004; Splawski et al., 2005).”
BackgroundIdentification of a Kir3.4 Mutation in Congenital Long QT Syndrome
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“However, several early studies demonstrated important differences in the ability of calcium influx through L-VGCCs versus NMDARs to activate specific transcriptional pathways (Bading et al., 1993; Ghosh et al., 1994b).”
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InfluentialMutations in the calcium-related gene IL1RAPL1 are associated with autism
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“In each of several unrelated cases, the same mutation (G406R in exon 8A of CACNA1C) was found, which is likely to cause intracellular Ca2+ overload in multiple cell types (Splawski et al., 2004) and reflects the importance of Cav1.”
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“One of these studies reports the Timothy syndrome, a new multisystem disorder, often associated to autism, which is due to a recurrent de novo CACNA1C calcium channel mutation (Splawski et al., 2004).”
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BackgroundLimpitikul, W. B., Dick, I. E., Tester, D. J., Boczek, N. J., Limphong, P., Yang, W., Choi, M. H., Babich, J., DiSilvestre, D. A., Kanter, R. J., et al. (2016) · Circulation Research · doi:10.1161/circresaha.116.309283 · Cited by 163
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“…has been to examine single gene mutations that share a high comorbidity with ASD such as fragile X syndrome, Tuberous sclerosis complex, Timothy Syndrome, Rett Syndrome, and Angelmen syndrome (Matsuura et al., 1997; Baker et al., 1998; Amir et al., 1999; Splawski et al., 2004; Hatton et al., 2006).”
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“…by a host of physical and or developmental abnormalities in addition to the classic phenotype of QT prolongation and an increased risk of SCD. [8 ] Furthermore, as our understanding of the genetic basis of LQTS continues to expand, it has become clear that LQTS, like many monogenic disorders,…”
Berger, S. M., & Bartsch, D. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-1936-3 · Cited by 166
“and psychiatric diseases came from a study investigating the genetics of Timothy syndrome (TS; Splawski et al. 2004).”
BackgroundGenetics of cardiac arrhythmias
Wilde, A. A. M., & Bezzina, C. R. (2005) · Heart · doi:10.1136/hrt.2004.046334 · Cited by 154
“LQTS type 7, also known as Andersen syndrome, is a rare disorder with cardiac manifestations that include mild QT interval prolongation and significant U waves, frequent ventricular ectopy, bidirectional ventricular tachycardia (VT), and more rarely syncope, recurrent polymorphic VT, and cardiac arrest. The syndrome a…”
BackgroundTester, D. J., Kopplin, L. J., Will, M. L., & Ackerman, M. J. (2005) · Heart Rhythm · doi:10.1016/j.hrthm.2005.07.012 · Cited by 155
Helbig, K. L., Lauerer, R. J., Bahr, J. C., Souza, I. A., Myers, C. T., Uysal, B., Schwarz, N., Gandini, M. A., Huang, S., Keren, B., et al. (2018) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2018.09.006 · Cited by 158
“Gly406Arg) in Timothy syndrome, a severe developmental disorder with fatal cardiac arrhythmia and autism.(6,7) Although most disease-causing variants cluster in S6 transmembrane segments, the identified p.”
BackgroundMajor channels involved in neuropsychiatric disorders and therapeutic perspectives
Imbrici, P., Camerino, D. C., & Tricarico, D. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00076 · Cited by 151
“In 2004, Splawski et al. (2004) described two mutations, G406R and G402S in the alternative splice exon 8 of Cav1.”
BackgroundYang, S., & Huang, X.-Y. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501625200 · Cited by 152
Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery
Imbrici, P., Liantonio, A., Camerino, G. M., Bellis, M. D., Camerino, C., Mele, A., Giustino, A., Pierno, S., Luca, A. D., Tricarico, D., et al. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2016.00121 · Cited by 151
“This drug can be effective in reducing stiffness and transient weakness in non-dystrophic myotonias and myotonic dystrophy (Statland et al., 2012; Lo Monaco et al., 2015).”
BackgroundWen, Y., Alshikho, M. J., & Herbert, M. R. (2016) · PLOS ONE · doi:10.1371/journal.pone.0153329 · Cited by 150
Mouse models of long QT syndrome
Salama, G., & London, B. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.118745 · Cited by 150
“The optical mapping technique has also been adapted to study the adult mouse conduction system and developmental changes in embryos and neonates (Tamaddon et al. 2000; Rentschler et al. 2001).”
MethodBhandari, R., Paliwal, J. K., & Kuhad, A. (2020) · Advances in neurobiology · doi:10.1007/978-3-030-30402-7_4 · Cited by 167
Alternative splicing: Human disease and quantitative analysis from high-throughput sequencing
Jiang, W., & Chen, L. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.12.009 · Cited by 170
Neuronal proteins custom designed by alternative splicing
Lipscombe, D. (2005) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2005.04.002 · Cited by 145
Antzelevitch, C. N., & Oliva, A. (2005) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2005.01587.x · Cited by 149
L-type calcium channel targeting and local signalling in cardiac myocytes.
Shaw, R., & Colecraft, H. M. (2013) · Cardiovascular Research · doi:10.1093/cvr/cvt021 · Cited by 150
Genetic and Clinical Advances in Congenital Long QT Syndrome
Mizusawa, Y., Horie, M., & Wilde, A. A. M. (2014) · Circulation Journal · doi:10.1253/circj.cj-14-0905 · Cited by 148
Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances
Fernández-Falgueras, A., Sarquella‐Brugada, G., Brugada, J., Brugada, R., & Campuzano, Ó. (2017) · Biology · doi:10.3390/biology6010007 · Cited by 146
Schlick, B., Flucher, B. E., & Obermair, G. J. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.02.037 · Cited by 144
“…change during development Because CaVs have been previously demonstrated to be important for neuronal maturation and development (Pravettoni et al., 2000; Splawski et al., 2004), we next sought to investigate whether and how their expression patterns change from late embryonic until adult stages.”
BackgroundNeuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS
Rajakulendran, S., Kaski, D. N., & Hanna, M. G. (2012) · Nature Reviews Neurology · doi:10.1038/nrneurol.2011.228 · Cited by 143
Predicting functional effects of missense variants in voltage-gated sodium and calcium channels
Heyne, H. O., Baez-Nieto, D., Iqbal, S., Palmer, D. S., Brunklaus, A., May, P., Collaborative, E., Johannesen, K. M., Lauxmann, S., Lemke, J. R., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay6848 · Cited by 140
“(Cannon, 2015; Mitrovi ć et al., 1994; Ptácek et al., 1992; Ptácek et al., 1991) SCN4A hypokalaemic periodic paralysis (HypoPP) LOF 1 electrophysiology (Bulman et al., 1999; Cannon, 2015; Matthews et al., 2009) SCN5A Brugada syndrome (heart) LOF electrophysiology, ECG (Chen et al., 1998)”
BackgroundGenetic aspects of autism spectrum disorders: insights from animal models
Banerjee, S., Riordan, M., & Bhat, M. A. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00058 · Cited by 156
Sudden arrhythmic death syndrome: a national survey of sudden unexplained cardiac death
Behr, E. R., Casey, A., Sheppard, M. N., Wright, M., Bowker, T. J., Davies, M. J., McKenna, W. J., & Wood, D. A. (2007) · Heart · doi:10.1136/hrt.2006.099598 · Cited by 139
The genetic architecture of long QT syndrome: A critical reappraisal
Giudicessi, J. R., Wilde, A. A. M., & Ackerman, M. J. (2018) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2018.03.003 · Cited by 141
Wayman, G. A., Bose, D. D., Yang, D., Lesiak, A. J., Bruun, D. A., Impey, S., Ledoux, V. A., Pessah, I. N., & Lein, P. J. (2012) · Environmental Health Perspectives · doi:10.1289/ehp.1104833 · Cited by 136
“2 that causes Timothy syndrome, which has a 60% rate of co- morbidity with autism (Splawski et al. 2004), making it one of the most penetrant monogenic forms of ASD.”
BackgroundL‐type calcium channels and psychiatric disorders: A brief review
Casamassima, F., Hay, A. C., Benedetti, A., Lattanzi, L., Cassano, G. B., & Perlis, R. H. (2010) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31122 · Cited by 139
“2 channels provoke phenotypes including cognitive impairment, mental retardation, and autistic features such as in Timothy syndrome, a devastating disorder also characterized by severemultiorgan abnormalities and global cognitive impairment [Splawski et al., 2004, 2005].”
BackgroundRegulation of Voltage-Gated Ca 2+ Channels by Calmodulin
Halling, D. B., Aracena-Parks, P., & Hamilton, S. L. (2005) · Science s STKE · doi:10.1126/stke.3152005re15 · Cited by 135
Klocke, C. R., & Lein, P. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031013 · Cited by 140
Pharmacology of L-type Calcium Channels: Novel Drugs for Old Targets?
Striessnig, J., Ortner, N. J., & Pinggera, A. (2015) · Current Molecular Pharmacology · doi:10.2174/1874467208666150507105845 · Cited by 143
Polyak, A., Kubina, R. M., & Girirajan, S. (2015) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32338 · Cited by 155
“For example, premorbid social impairment or pervasive developmental disorders (PDD) have been observed in 50– 87% of individuals with childhood-onset schizophrenia [Sporn et al., 2004; Rapoport et al., 2009; King and Lord, 2011; Gadow, 2012; Cristino et al., 2014].”
BackgroundGargus, J. J. (2008) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2008.03572.x · Cited by 134
Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels
Striessnig, J., Bolz, H. J., & Koschak, A. (2010) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-010-0800-x · Cited by 135
“2, VDI is also inhibited by mutation of nearby residues such as a serine residue important for slow inactivation in IS6 and G406 in Timothy syndrome (G406R) [72].”
BackgroundIon Channel Functions in Early Brain Development
Smith, R. S., & Walsh, C. A. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2019.12.004 · Cited by 133
“Ca channel subunits are also implicated in wide-ranging postnatal channelopathies, including CACNA1A and CACNA1E in DE and EE [74,75], CACNA4A in familial hemiplegic migraine and episodic ataxia [76], and CACNA1C in Timothy syndrome, which includes autism phenotypes [77].”
BackgroundHemara‐Wahanui, A., Berjukow, S., Hope, C., Dearden, P. K., Wu, S., Wilson-Wheeler, J. C., Sharp, D. M., Lundon-Treweek, P., Clover, G. M., Hoda, J., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501907102 · Cited by 132
Yeh, E., Ng, S., Zhang, M., Bouhours, M., Wang, Y., Wang, M., Hung, W., Aoyagi, K., Melnik-Martínez, K. V., Li, M., et al. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060055 · Cited by 131
“In several cases, these gain-of-function mutations lead to slowed inactivation, subsequently prolonging the duration of the corresponding currents [18,39,40].”
BackgroundEffect of CACNA1C rs1006737 on neural correlates of verbal fluency in healthy individuals
Krug, A., Nieratschker, V., Markov, V., Krach, S., Jansen, A., Zerres, K., Eggermann, T., Stöcker, T., Shah, N. J., Treutlein, J., et al. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.09.028 · Cited by 129
“Furthermore, non-synonymous mutations in CACNA1C have been found to cause Timothy syndrome, a multiorgan dysfunction including heart failures, cognitive impairments – comprising deficits in language skills – and autism spectrum disorders (Splawski et al., 2005, 2004).”
Adams, D. S., Uzel, S. G. M., Akagi, J., Włodkowic, D., Andreeva, V., Yelick, P. C., Devitt‐Lee, A., Paré, J., & Levin, M. G. (2016) · The Journal of Physiology · doi:10.1113/jp271930 · Cited by 125
“…in: the calcium channel CACNA1C that causes Timothy Syndrome, a cardiac insufficiency accompanied by syndactyly and CFAs like those seen in ATS (Splawski et al. 2004); ANKH, an anion transporter associated with craniometaphyseal dysplasia (Kornak et al. 2010); KCNK9, which causes Birk–Barel…”
Background
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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