Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations
Igor Splawski,Katherine W. Timothy,Katherine W. Timothy,Niels Decher,Pradeep Kumar,Frank B. Sachse,Alan H. Beggs,Michael C. Sanguinetti,Mark T. Keating,Mark T. Keating +9 more
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TLDR
In this article, the authors identified de novo missense mutations in exon 8 of the spliced form of CaV1.2 in both individuals, which resulted in extreme prolongation of the QT interval on electrocardiogram.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 (CaV1.2) 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 CaV1.2 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 CaV1.2 containing exon 8 is highly expressed in heart and brain, accounting for ≈80% of CaV1.2 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 CaV1.2 exons 8 and 8A cause distinct forms of TS.read more
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Journal ArticleDOI
Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death
Charles Antzelevitch,Guido D. Pollevick,Jonathan M. Cordeiro,Oscar Casis,Michael C. Sanguinetti,Yoshiyasu Aizawa,Alejandra Guerchicoff,Ryan Pfeiffer,Antonio Oliva,Bernd Wollnik,Philip Gelber,Elias P. Bonaros,Elena Burashnikov,Yuesheng Wu,John D. Sargent,Stefan Schickel,Ralf Oberheiden,Atul Bhatia,Li Fern Hsu,Michel Haïssaguerre,Rainer Schimpf,Martin Borggrefe,Christian Wolpert +22 more
TL;DR: This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.
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Assembly of functionally integrated human forebrain spheroids
Fikri Birey,Jimena Andersen,Christopher D. Makinson,Saiful Islam,Wu Wei,Nina Huber,H. Christina Fan,Kimberly R. Cordes Metzler,Georgia Panagiotakos,Nicholas Thom,Nancy A. O'Rourke,Lars M. Steinmetz,Lars M. Steinmetz,Jonathan A. Bernstein,Joachim Hallmayer,John R. Huguenard,Sergiu P. Paşca +16 more
TL;DR: Three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons are generated and it is found that in Timothy syndrome—a neurodevelopmental disorder caused by mutations in the CaV1.2 calcium channel—interneurons display abnormal migratory saltations.
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The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential
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Journal ArticleDOI
Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome
Masayuki Yazawa,Brian Hsueh,Brian Hsueh,Xiaolin Jia,Xiaolin Jia,Anca M. Pasca,Anca M. Pasca,Jonathan A. Bernstein,Joachim Hallmayer,Ricardo E. Dolmetsch +9 more
TL;DR: In this paper, the effect of Timothy syndrome mutation on the electrical activity and contraction of human cardiomyocytes was explored, and roscovitine, a compound that increases the voltage-dependent inactivation of Ca(V)1.2, was found to restore the electrical and Ca(2+) signalling properties of Cardiomyocyte from Timothy syndrome patients.
Journal ArticleDOI
Neuronal Voltage-Gated Calcium Channels: Structure, Function, and Dysfunction
Brett A. Simms,Gerald W. Zamponi +1 more
TL;DR: Attention is focused on salient aspects of voltage-gated calcium channel function, physiology, and pathophysiology that are of critical importance to brain function.
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Journal ArticleDOI
Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.
Igor Splawski,Katherine W. Timothy,Leah M. Sharpe,Niels Decher,Pradeep Kumar,Raffaella Bloise,Carlo Napolitano,Peter J. Schwartz,Robert M. Joseph,Karen Condouris,Helen Tager-Flusberg,Silvia G. Priori,Michael C. Sanguinetti,Mark T. Keating +13 more
TL;DR: Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation, which likely induces intracellular Ca( 2+) overload in multiple cell types.
Journal ArticleDOI
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Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death
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