title: Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S2-S3 inner loop of HERG.
abstract: Long QT syndrome is a congenital disorder that presents with a defective cardiac ion channel and is either associated with prolonged action potential or, more commonly, known as an acquired form in which "torsades de pointes" type arrhythmias specifically occur after secondary causes. We report a case of a novel HERG mutation (A490T) that caused a bradycardia-associated form of long QT syndrome. A 27-year-old woman exhibited recurrent syncope due to torsades de pointes associated with a disturbance of the cardiac conduction system. By using polymerase chain reaction and single strand conformational polymorphism analyses, we identified a heterozygous single nucleotide substitution of HERG (G to A at nt 1468). This mutational change was not present in 140 Japanese control individuals. Electrophysiological assays for the A490T mutant HERG channel were conducted in the heterologous expression system with COS7 cells. The mutant channel was found to reconstitute functional channel currents, suggesting the homomeric mutant channel was functional. The mutation did not change the properties of the activation gate and inward rectification, however the current density of this mutant channel was small compared with that of wild type HERG. Taken together, this mutant may cause subtle changes in HERG channel functions (I(Kr)) in vivo. In this case, genetic background and unexpected bradycardia may have contributed to the development of long QT syndrome.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Shogoin Kawara 54, Sakyo, Kyoto, 606-8507, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.forename: M
authors.initials: M
authors.lastname: Horie
authors.forename: H
authors.initials: H
authors.lastname: Otani
authors.forename: T
authors.initials: T
authors.lastname: Kawashima
authors.forename: Y
authors.initials: Y
authors.lastname: Onishi
authors.forename: S
authors.initials: S
authors.lastname: Sasayama
mesh_terms: D000328:Adult; D001919:Bradycardia / Q000150:complications*; D027682:Cation Transport Proteins; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D020125:Mutation, Missense; D018807:Polymorphism, Single-Stranded Conformational; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D004247:DNA