title: Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.
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 approximately 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, and Genomics Program and Division of Genetics, Children's Hospital, Boston, MA 02115, USA. igor@enders.tch.harvard.edu
authors.forename: Igor
authors.initials: I
authors.lastname: Splawski
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Timothy
authors.forename: Niels
authors.initials: N
authors.lastname: Decher
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.forename: Frank B
authors.initials: FB
authors.lastname: Sachse
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: Mark T
authors.initials: MT
authors.lastname: Keating
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002675:Child, Preschool; D004594:Electrophysiology; D005091:Exons / Q000235:genetics; D005260:Female; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009865:Oocytes / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome; D014981:Xenopus
chemical_list: D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D005998:Glycine