CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism
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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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Clear evidence from Timothy syndrome shows that improper Ca2+ channel function can cause ASD with penetrance as high as 60-80%.
“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
Over 60% of TS patients also fulfill the criteria for an autism spectrum disorder (ASD).
“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]
Timothy syndrome is caused by a missense mutation in the L-type calcium channel Cav1.2 that is associated with developmental delay and autism.
“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]
TS is caused by a point mutation in an alternatively spliced exon of CACNA1C, the gene that encodes the α1 subunit of Cav1.2.
“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]
This mutation leads to decreased calcium- and voltage-dependent inactivation of the channel.
“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]
Mutations in voltage-gated L-type calcium channels that flux calcium to initiate activity-dependent gene transcription are associated with Timothy syndrome, which has a significant association with ASD phenotypes.
“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 mice, this missense mutation leads to increased Ca2+ currents and loss of voltage-dependent channel inactivation.
“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]
Timothy syndrome, characterized by cardiac arrhythmia, congenital heart disease, immune deficiency, intermittent hypoglycaemia, global development delay, and ASD, is caused by a missense mutation in CACNA1C.
“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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BackgroundThe Jervell and Lange-Nielsen Syndrome
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“These mutations are described as gain of function (Table 1), as they involve loss of channel inactivation, which results in elevated Ca2+ entry (Splawski et al., 2004; Barrett and Tsien, 2008; Ramachandran et al., 2013).”
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Self-citation
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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