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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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“…ow nloaded from http://rupress.org/jgp/article-pdf/151/6/786/1236937/jgp_201812236.pdf by guest on 16 O ctober 2021 Conversely, the G406R mutation linked to Timothy syndrome (Faber et al., 2007) has been shown to reduce VDI (Splawski et al., 2004), thus isolating CDI.”
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“In humans, the importance of Ca(2) channel inactivation is underscored by the rare disease, Timothy Syndrome, in which a defect in the voltage-dependent component of the L-type Ca(2) channel inactivation leads to profound QT prolongation, arrhythmias, and sudden cardiac death at a young age (65).”
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“2 channels simulating heterozygous and homozygous states of TS1 and TS2 (20, 21) produced 1) progressive prolongation of APD and QT interval, accompanied by amplification of TDR, steepening of APD restitution, and inducible transient concordant APD alternans; 2) readily inducible EADs, DADs, and DAD-mediated triggered…”
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“2 calcium channel mutations present with similar craniofacial and digit abnormalities causing Timothy syndrome (Splawski et al., 2004; Diep and Seaver, 2015).”
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“First, a genetic approach was used to increase L-type voltage-gated Ca2+ entry during chamber formation by expression of the Timothy Syndrome mutant CaV1.”
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Elevated basal transcription can underlie timothy channel association with autism related disorders
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Deciphering the physiopathology of neurodevelopmental disorders using brain organoids
Dionne, O., Sabatié, S., & Laurent, B. (2024) · Brain · doi:10.1093/brain/awae281 · Cited by 22
Horigane, S., Ozawa, Y., Zhang, J., Todoroki, H., Pan, M., Haijima, A., Yanagawa, Y., Ueda, S., Nakamura, S., Kakeyama, M., et al. (2020) · FEBS Open Bio · doi:10.1002/2211-5463.12924 · Cited by 19
CaV1.2 channelopathic mutations evoke diverse pathophysiological mechanisms
Bamgboye, M. A., Herold, K., Vieira, D. C. O., Traficante, M. K., Rogers, P. J., Johny, M. B., & Dick, I. E. (2022) · The Journal of General Physiology · doi:10.1085/jgp.202213209 · Cited by 20
Gao, J., Makiyama, T., Yamamoto, Y., Kobayashi, T., Aoki, H., Maurissen, T. L., Wuriyanghai, Y., Kashiwa, A., Imamura, T., Aizawa, T., et al. (2023) · Circulation Arrhythmia and Electrophysiology · doi:10.1161/circep.122.011387 · Cited by 20
The Genetic and Clinical Features of Cardiac Channelopathies
Roberts, J. D., & Gollob, M. H. (2010) · Future Cardiology · doi:10.2217/fca.10.27 · Cited by 20
“LQT8, or Timothy’s syndrome, occurs secondary to gain‑of‑function mutations within CACNA1c, which encodes an L‑type calcium channel responsible for calcium current (I Ca ) (Figure 1) [22].”
BackgroundInfluentialCalcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels
Cohen-Kutner, M., Yahalom, Y., Trus, M., & Atlas, D. (2012) · Scientific Reports · doi:10.1038/srep00366 · Cited by 21
“In TS, VDI impairment resulted in prolonged QT interval, and severe arrhythmias in the heart, accompanied by an autism spectrum disorde”
BackgroundAnchored protein kinase A signalling in cardiac cellular electrophysiology
Soni, S., Scholten, A., Vos, M. A., & van Veen, T. A. B. (2014) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12365 · Cited by 20
Copy number variation in fetal alcohol spectrum disorder
Zarrei, M., Hicks, G. G., Reynolds, J. N., Thiruvahindrapuram, B., Engchuan, W., Pind, M., Lamoureux, S., Wei, J., Wang, Z., Marshall, C. R., et al. (2018) · Biochemistry and Cell Biology · doi:10.1139/bcb-2017-0241 · Cited by 22
Ozawa, J., Ohno, S., Saito, H., Saitoh, A., Matsuura, H., & Horie, M. (2018) · HeartRhythm Case Reports · doi:10.1016/j.hrcr.2018.03.003 · Cited by 17
“Introduction Timothy syndrome (TS) is a rare multisystem disorder associated with long QT syndrome (LQTS, type 8), congenital heart disease, syndactyly, dysmorphic facial features, and neurologic symptoms including autism, seizures, and intellectual disability.(1) Classical TS is caused by a recurrent de novo CaV1.”
BackgroundThe CaV1.2 L-type calcium channel regulates bone homeostasis in the middle and inner ear
Cao, C., Oswald, A. B., Fabella, B. A., Ren, Y., Rodriguiz, R. M., Trainor, G. L., Greenblatt, M. B., Hilton, M. J., & Pitt, G. S. (2019) · Bone · doi:10.1016/j.bone.2019.05.024 · Cited by 20
Mellor, G. J., Panwar, P., Lee, A. K., Steinberg, C., Hathaway, J., Bartels, K. L., Christian, S., Balaji, S., Roberts, J. D., Simpson, C. S., et al. (2019) · EP Europace · doi:10.1093/europace/euz215 · Cited by 20
The cardiac L-type calcium channel distal carboxy terminus autoinhibition is regulated by calcium
Crump, S. M., Andres, D., Sievert, G., & Satin, J. (2012) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00396.2012 · Cited by 21
Toward a hierarchy of mechanisms in CaMKII-mediated arrhythmia
Vincent, K. P., McCulloch, A. D., & Edwards, A. G. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00110 · Cited by 23
“402; Splawski et al., 2004, 2005).”
BackgroundInfluentialTuluc, P., & Flucher, B. E. (2011) · Journal of Muscle Research and Cell Motility · doi:10.1007/s10974-011-9270-9 · Cited by 20
“Computer modeling of cardiac myocytes demonstrated that particularly the delayed inac- tivation prolongs the cardiac action potential similarly to long QT syndromes and Timothy disease (Splawski et al. 2004, 2005; Tuluc et al. 2007).”
L-type Calcium Channel Cav1.2 Is Required for Maintenance of Auditory Brainstem Nuclei
Ebbers, L., Satheesh, S. V., Janz, K., Rüttiger, L., Blosa, M., Hofmann, F. B., Morawski, M., Griesemer, D., Knipper, M., Friauf, E., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.672675 · Cited by 21
“2, are associated with Timothy syndrome, characterized by cardiac arrhythmia, syndactyly, cognitive abnormalities, and autism (17), Brugada syndrome-3 (18), associated with shorter QT intervals or early repolarization syndrome with an abnormal electroencephalography pattern (19).”
BackgroundEffect of knockout of α 2 δ-1 on action potentials in mouse sensory neurons
Margas, W., Ferron, L., Nieto‐Rostro, M., Schwartz, A., & DOLPHIN, A. C. (2016) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2015.0430 · Cited by 21
Wei, X., Yu, S., Ren, L., Huang, S.-H., Yang, Q.-M., Wang, P., Chu, Y., Yang, W., Ding, Y., Huo, Y., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-01056-0 · Cited by 20
Man, K. N. M., Navedo, M. F., Horne, M. C., & Hell, J. W. (2019) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010919-023404 · Cited by 20
Predicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium ChannelsPreprint
Heyne, H., Báez-Nieto, D., Iqbal, S., Palmer, D. S., Brunklaus, A., Collaborative, T. E., Johannesen, K. M., Lauxmann, S., Lemke, J. R., Møller, R. S., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/671453 · Cited by 20
From Organoids to Assembloids: Experimental Approaches to Study Human Neuropsychiatric Disorders
Levy, R. J., & Pașca, S. P. (2025) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-112723-023232 · Cited by 24
Gardner, R. M. M., Crozier, I., Binfield, A. L., Love, D. R., Lehnert, K., Gibson, K., Lintott, C., Snell, R. G., Jacobsen, J., Jones, P. P., et al. (2018) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.476 · Cited by 18
“The only familial examples were siblings with p.G402S born to a mosaic, unaffected father, and siblings with p.G406R born to a mosaic, unaffected mother (Fröhler et al., 2014; Splawski et al., 2004).”
BackgroundKuo, C.-W. S., Dobi, S., Gök, Ç., Costa, A. D. S., Main, A., Robertson-Gray, O., Baptista‐Hon, D. T., Wypijewski, K. J., Costello, H. M., Hales, T. G., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2207887120 · Cited by 20
“This rightward shift of the Ca(v)1.2 voltage activation curve is consistent with reduced Ca 2+ entry in iPSC-derived CMs, reducing the amplitude of the Ca 2+ transient while simultaneously prolonging the transients because the extent of CDI is reduced. of α 1C profoundly alter Ca(v)1.2 behavior, causing Brugada (31) a…”
BackgroundInfluentialBaker, M. R., Lee, A. S., & Rajadhyaksha, A. M. (2023) · Channels · doi:10.1080/19336950.2023.2176984 · Cited by 21
Blood brain barrier: the role of calcium homeostasis.
Yarlagadda, A., Kaushik, S., & Clayton, A. H. (2007) · PubMed Central · Cited by 19
Congenital long QT syndromes: clinical features, molecular genetics and genetic testing
Ching, C., & Tan, E. (2006) · Expert Review of Molecular Diagnostics · doi:10.1586/14737159.6.3.365 · Cited by 19
Neuronal cell‐type specific DNA methylation patterns of the Cacna1c gene
Nishioka, M., Shimada, T., Bundo, M., Ukai, W., Hashimoto, E., Saito, T., Kano, Y., Sasaki, T., Kasai, K., Kato, T., et al. (2012) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2012.11.007 · Cited by 19
“physical malformations, and autistic symptoms (Splawski et al., 2004).”
Sudden Cardiac Death: The Larger Problem… the Larger Genome
Spooner, P. M. (2009) · Journal of Cardiovascular Electrophysiology · doi:10.1111/j.1540-8167.2008.01419.x · Cited by 19
Genetics and Arrhythmias: Diagnostic and Prognostic Applications
Monteforte, N., Napolitano, C., & Priori, S. G. (2012) · Revista Española de Cardiología (English Edition) · doi:10.1016/j.rec.2011.10.010 · Cited by 19
Self-citationCooperative and acute inhibition by multiple C-terminal motifs of L-type Ca2+ channels
Liu, N., Yang, Y., Ge, L., Liu, M., Colecraft, H. M., & Liu, X. (2017) · eLife · doi:10.7554/elife.21989 · Cited by 17
“For instance, channel mutations in congenital diseases, e.g., Timothy syndrome (Splawski et al., 2004), could cause less inactivation in ICa and thus elevate the Ca 2+ entries.”
BackgroundGenetics update: Monogenetics, polygene disorders and the quest for modifying genes
Symonds, J. D., & Zuberi, S. M. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.10.013 · Cited by 19
“2007) (Splawski et al. 2004) Brugada syndrome Dominant LOF β2 subunit of the L type voltage-gated calcium channel Voltage Calcium CACNB2 (Antzelevitch et al.”
BackgroundMartinez‐Ortiz, W., & Cardozo, T. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.04.024 · Cited by 19
“…JurkatRott et al., 1994, 2002; Khosravani et al., 2005; Mantuano et al., 2004; McRory et al., 2004; Ophoff et al., 1996; Ptácek et al., 1994; Spacey et al., 2004; Splawski et al., 2004, 2005, 2006; Striessnig et al., 2004; Strom et al., 1998; Vitko et al., 2005; Wallace, 1986; Wappl et al., 2002).”
Bartels, P., Yu, D.-J., Huang, H., Hu, Z., Herzig, S., & Soong, T. (2018) · Biophysical Journal · doi:10.1016/j.bpj.2018.03.029 · Cited by 18
Luo, J., & Li, P. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00617-1 · Cited by 20
“Timothy syndrome (TS) is another neurodevelopmental disorder characterized by epilepsy [80].”
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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