title: A homozygous SCN5A mutation in a severe, recessive type of cardiac conduction disease.
abstract: Cardiac sodium channels are key players in the generation and propagation of action potentials in the human heart. Heterozygous mutations in the SCN5A gene have been found to be associated with long QT syndrome, Brugada syndrome, and sinus node dysfunction (SND). Recently, overlapping arrhythmia phenotypes have been reported as well. Here we describe a novel recessive SCN5A mutation in a family originating from the German minority in White Russia. Four affected children with a history of early cardiac arrhythmia encompassing SND, conduction disease, and severe ventricular arrhythmias, are homozygous carriers of a novel SCN5A missense mutation (p.I230T) in the channel protein. Interestingly, the heterozygous mutation carriers had neither significant ECG abnormalities nor a history of cardiac events. Heterologous expression of SCN5A(I230T) channels revealed normal protein transport but altered biophysical sodium channel properties. Voltage range of both activation and inactivation were shifted in a way that resulted in decreased sodium current and loss of channel function. In conclusion, we describe a rare clinical condition with a novel SCN5A mutation causing a new type of complex cardiac arrhythmia. Unlike most previously reported sodium channelopathies, this overlap syndrome displays recessive inheritance characteristics and does not seem to follow simple Mendelian rules.
authors.affiliation: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Neu
authors.forename: Michele
authors.initials: M
authors.lastname: Eiselt
authors.forename: Matthias
authors.initials: M
authors.lastname: Paul
authors.forename: Kathrin
authors.initials: K
authors.lastname: Sauter
authors.forename: Birgit
authors.initials: B
authors.lastname: Stallmeyer
authors.forename: Dirk
authors.initials: D
authors.lastname: Isbrandt
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
mesh_terms: D000293:Adolescent; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000000981:diagnostic imaging / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D017809:Fatal Outcome; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D005858:Germany / Q000208:ethnology; D006329:Heart Conduction System / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D042541:Intracellular Space / Q000378:metabolism; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D021381:Protein Transport; D002094:Republic of Belarus; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D009124:Muscle Proteins; D050505:Mutant Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels