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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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“The effects of noncovalently bound DCT on peak cur rent amplitude and VDI required Mgi binding to the proximal Cterminal EFhand and were prevented by muta tions of a key divalent cationbinding amino acid residue.”
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“Exon 8 and its mutually exclusive splicing counterpart, exon 8A, harbor pathogenic mutations in Timothy syndrome, characterized by developmental delays, neuropsychiatric comorbidities, and long QT syndrome (39, 40).”
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“The genetic defects in ICa,L have been linked with LQTS [16], Brugada syndrome [17], ERS [8, 9] and SQTS [18].”
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“18,38).”
InfluentialFunctional Characterization of CaVα2δ Mutations Associated with Sudden Cardiac Death*
Bourdin, B., Shakeri, B., Tetreault, M., Sauvé, R., Lesage, S., & Parent, L. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.597930 · Cited by 31
“Timothy syndromes 1 and 2 are rare variants of the long QT syndrome (LQT8) (24, 25) characterized by extreme QT-prolongation and gain-of-function mutations in the pore-forming subunit of CaV1.”
BackgroundBett, G. C. L., Lis, A., Wersinger, S. R., Baizer, J. S., Duffey, M. E., & Rasmusson, R. L. (2012) · North American Journal of Medicine and Science · doi:10.7156/najms.2012.053135 · Cited by 37
Voltage-gated Calcium Channels and Autism Spectrum Disorders
Breitenkamp, A. F., Matthes, J., & Herzig, S. (2015) · Current Molecular Pharmacology · doi:10.2174/1874467208666150507105235 · Cited by 36
Prakash, B., Priya, N., Abhilash, S., Vineetha, R. C., & Nair, R. H. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.04.087 · Cited by 36
Enhanced oligodendrocyte maturation and myelination in a mouse model of Timothy syndrome
Cheli, V. T., González, D. A. S., Zamora, N. N., Lama, T. N., Spreuer, V., Rasmusson, R. L., Bett, G. C. L., Panagiotakos, G., & Paez, P. M. (2018) · Glia · doi:10.1002/glia.23468 · Cited by 36
MicroRNA-Based Therapeutic Perspectives in Myotonic Dystrophy
López, A., Overby, S. J., & Artero, R. D. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225600 · Cited by 36
Autism - A Neurodevelopmental Journey from Genes to Behaviour
Eapen, V. (2011) · InTech eBooks · doi:10.5772/974 · Cited by 36
Genetics of channelopathies associated with sudden cardiac death
Campuzano, Ó., Sarquella‐Brugada, G., Brugada, R., & Brugada, J. (2015) · Global Cardiology Science and Practice · doi:10.5339/gcsp.2015.39 · Cited by 36
“This gives rise to an ECG with an extremely long QT interval.(55) Recently, a few cases of LQT syndrome have been identified in two genes: CALM1 and CALM2.”
BackgroundSignaling Complexes of Voltage-Gated Calcium Channels and G Protein-Coupled Receptors
Altier, C., & Zamponi, G. W. (2008) · Journal of Receptors and Signal Transduction · doi:10.1080/10799890801941947 · Cited by 36
NS ‐Pten knockout mice show sex‐ and age‐specific differences in ultrasonic vocalizations
Binder, M. S., & Lugo, J. N. (2017) · Brain and Behavior · doi:10.1002/brb3.857 · Cited by 36
“For Cowden syndrome, which involves a mutation in the phosphatase PTEN, several conditional knockouts have been created.”
BackgroundInfluentialSculpting ion channel functional expression with engineered ubiquitin ligases
Kanner, S. A., Morgenstern, T. J., & Colecraft, H. M. (2017) · eLife · doi:10.7554/elife.29744 · Cited by 36
“2) Timothy syndrome (Splawski et al., 2004); (TrpV4) heritable skeletal dysplasia (Rock et al., 2008); (KCNQ1 and HERG) short QT syndrome and familial atrial fibrillation (Giudicessi and Ackerman, 2012).”
BackgroundPatient-Specific Induced Pluripotent Stem Cells for Disease Modeling and Phenotypic Drug Discovery
Tang, S., Xie, M., Cao, N., & Ding, S. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00789 · Cited by 37
Presynaptic Calcium Channels: Structure, Regulators, and Blockers
Kisilevsky, A. E., & Zamponi, G. W. (2007) · Handbook of experimental pharmacology · doi:10.1007/978-3-540-74805-2_3 · Cited by 35
Brennan, S. C., Finney, B. A., Lazarou, M., Rosser, A., Scherf, C., Adriaensen, D., Kemp, P. J., & Riccardi, D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080294 · Cited by 35
“2 (cardiac L-type) was expressed in the developing heart, brain and neuronal outgrowths on the spinal cord [26] (Figure 3A and 3B).”
BackgroundRecent advances in genetic testing and counseling for inherited arrhythmias
Mizusawa, Y. (2016) · Journal of Arrhythmia · doi:10.1016/j.joa.2015.12.009 · Cited by 36
Metabolic Syndrome and Ionic Channels in Pancreatic Beta Cells
Hiriart, M., Velasco, M., Larqué, C., & Díaz‐García, C. M. (2014) · Vitamins and hormones · doi:10.1016/b978-0-12-800174-5.00004-1 · Cited by 34
“2 channels makes the beta cell secrete insulin excessively, causing hypoglycemic episodes in children with this mutation (Splawski et al., 2004).”
BackgroundRobert, C., Pasquier, L., Cohen, D., Fradin, M., Canitano, R., Damaj, L., Odent, S., & Tordjman, S. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18030618 · Cited by 36
“3) [191,196–222] 0–8 0–33 Variable Poor eye contact , social anxiety, language deficit and stereotypies Hyperactivity with attention deficit, sensory hyper-reactivity Facial dysmorphism, macro-orchidism Neurofibromatosis type 1 [109,223–225] NA 21–40 inconstant Restrictive/repetitive behaviors and severe social-commun…”
BackgroundInfluentialCacna1c(Cav1.2) Modulates Electroencephalographic Rhythm and Rapid Eye Movement Sleep Recovery
Kumar, D., Dedic, N., Flachskamm, C., Voulé, S., Deussing, J. M., & Kimura, M. (2015) · SLEEP · doi:10.5665/sleep.4972 · Cited by 35
Wright, D. J., Hall, N., Irish, N., Man, A., Glynn, W., Mould, A. W., Angeles, A. D. L., Angiolini, E., Swarbreck, D., Gharbi, K., et al. (2022) · BMC Genomics · doi:10.1186/s12864-021-08261-2 · Cited by 39
“Alternatively, AS can alter disease presentation, as is seen in the case of Timothy Syndrome where the localisation of the disease-causing mutation in one of two mutually exclusive exons of CACNA1C determines syndrome severity (Splawski et al. 2004).”
BackgroundHoda, J., Zaghetto, F., Singh, A., Koschak, A., & Striessnig, J. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03678.x · Cited by 35
“2; Kraus et al. 1998; Hans et al. 1999; Mullner et al. 2004; Splawski et al. 2004), the mutations characterized here provide valuable insight into the structure–function relationship of a1 subunits.”
BackgroundGodiksen, M. T. N., Stoevring, B., Behr, E. R., Ravn, L. S., McKenna, W. J., & Christiansen, M. (2006) · Clinica Chimica Acta · doi:10.1016/j.cca.2006.06.020 · Cited by 35
Schwartz, P. J., & Crotti, L. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.10.009 · Cited by 35
Self-citationGenetics of Sudden Cardiac Death
Barsheshet, A., brenyo, A. J., Moss, A. J., & Goldenberg, I. (2011) · Current Cardiology Reports · doi:10.1007/s11886-011-0209-y · Cited by 34
The zebrafish:scalable in vivo modeling for systems biology
Deo, R. C., & MacRae, C. A. (2010) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.117 · Cited by 34
Intragenic deletions of IL1RAPL1: Report of two cases and review of the literature
Behnecke, A., Hinderhofer, K., Bartsch, O., Nümann, A., Ipach, M., Damatova, N., Haaf, T., Dufke, A., Rieß, O., & Moog, U. (2010) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.33656 · Cited by 34
“N O S, pe rv as iv e de ve lo pm en ta l di so rd er — n ot ot he rw is e sp ec ifi ed ; XC I, Xch ro m os om e in ac ti va ti on an al ys is . have been associatedwith autistic phenotypes [Splawski et al., 2004, 2006; Hope et al., 2005].”
BackgroundMaternal Mosaicism Confounds the Neonatal Diagnosis of Type 1 Timothy Syndrome
Dufendach, K., Giudicessi, J. R., Boczek, N. J., & Ackerman, M. J. (2013) · PEDIATRICS · doi:10.1542/peds.2012-2941 · Cited by 34
“The genetic phenomenon ofmosaicism, whereby 2 genetically distinct populations of cells coexist within an individual’s somatic cells or gametes, has been observed in TS1 individuals/ families on at least 3 separate occasions.(1,2,7) These individuals are classified as having somatic and/or germline mosaicism according…”
BackgroundKeefe, J. A., Moore, O. M., Ho, K. S., & Wehrens, X. H. T. (2022) · Archives of Toxicology · doi:10.1007/s00204-022-03385-0 · Cited by 32
Zhang, H. Y., Liao, P. H., Wang, J. J., Yu, D. J., & Soong, T. W. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00798.x · Cited by 34
“The well known mutations in patients with Timothy syndrome have also been located at the beginning of the I–II loop (Splawski et al., 2004; 2006).”
BackgroundAckerman, M. J. (2005) · Seminars in Pediatric Neurology · doi:10.1016/j.spen.2005.02.002 · Cited by 35
Clinical and Laboratory Data in a Sample of Greek Children with Autism Spectrum Disorders
Ververi, A., Vargiami, E., Papadopoulou, V., Tryfonas, D., & Zafeiriou, D. (2011) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-011-1414-7 · Cited by 37
Andrade, A., Sandoval, A., González‐Ramírez, R., Lipscombe, D., Campbell, K. P., & Felix, R. (2009) · Cell Calcium · doi:10.1016/j.ceca.2009.08.006 · Cited by 34
What can naturally occurring mutations tell us about Cav1.x channel function?
Stockner, T., & Koschak, A. (2012) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2012.11.026 · Cited by 35
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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