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Cited by 624Cardiac electrophysiology and arrhythmiasIon channel regulation and functionGenomics and Rare Diseases

Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations

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Splawski, Igor, Timothy, Katherine W., Decher, Niels, Kumar, Pradeep, Sachse, Frank B., Beggs, Alan H., Sanguinetti, Michael C., Keating, Mark T.·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0502506102PMC PMC1149428
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Abstract

Timothy syndrome (TS) is a multisystem disorder that causes syncope and sudden death from cardiac arrhythmias. Prominent features include congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. All TS individuals have syndactyly (webbing of fingers and toes). We discovered that TS resulted from a recurrent, de novo cardiac L-type calcium channel (Ca V 1.2) mutation, G406R. G406 is located in alternatively spliced exon 8A, encoding transmembrane segment S6 of domain I. Here, we describe two individuals with a severe variant of TS (TS2). Neither child had syndactyly. Both individuals had extreme prolongation of the QT interval on electrocardiogram, with a QT interval corrected for heart rate ranging from 620 to 730 ms, causing multiple arrhythmias and sudden death. One individual had severe mental retardation and nemaline rod skeletal myopathy. We identified de novo missense mutations in exon 8 of Ca V 1.2 in both individuals. One was an analogous mutation to that found in exon 8A in classic TS, G406R. The other mutation was G402S. Exon 8 encodes the same region as exon 8A, and the two are mutually exclusive. The spliced form of Ca V 1.2 containing exon 8 is highly expressed in heart and brain, accounting for ≈80% of Ca V 1.2 mRNAs. G406R and G402S cause reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia. These data indicate that gain-of-function mutations of Ca V 1.2 exons 8 and 8A cause distinct forms of TS.

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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., 2005

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Authors
Splawski, I., Timothy, K. W., Decher, N., Kumar, P., Sachse, F. B., Beggs, A. H., Sanguinetti, M. C., & Keating, M. T.
Affiliations
Howard Hughes Medical Institute (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-04-29
Volume
102
Issue
23
Pages
8089-8096
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0502506102
PMC
PMC1149428
OpenAlex
W2019028325
Cited by
624
References
27
Citations by year
2026: 7 · 2025: 19 · 2024: 20 · 2023: 18 · 2022: 30 · 2021: 27 · 2020: 38 · 2019: 28 · 2018: 30 · 2017: 36 · 2016: 27 · 2015: 31 · 2014: 39 · 2013: 46 · 2012: 45
FWCI
20.28
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Donald W. Reynolds Foundation
  • Charles H. Hood Foundation
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL46401, T-32 HL07572, HL-52338, R01HL044365, R01HL046401, P50HL052338, T32HL007572)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR044345, AR-44345)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655, P30HD-18655)
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
Timothy syndrome, L-type calcium channels, Cav1.2, de novo missense variant, QT prolongation, sudden cardiac death, cardiac arrhythmias, exon 8, alternative splicing, channel inactivation, delayed afterdepolarizations, intellectual disability, gain-of-function mutations
MeSH terms
Action Potentials, Amino Acid Sequence, Animals, Arrhythmias, Cardiac, Brain, Child, Preschool, Electrophysiology, Exons, Female, Glycine, Humans, Infant, Infant, Newborn, Male, Molecular Sequence Data, Myocardium, Oocytes, Pedigree, Phenotype, Syndrome, Xenopus, Mutation, Missense, Calcium Channels, L-Type

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