title: Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.
abstract: Hyperpolarization-activated cyclic nucleotide-gated channel 4 gene HCN4 is a pacemaker channel that plays a key role in automaticity of sinus node in the heart, and an HCN4 mutation was reported in a patient with sinus node dysfunction. Expression of HCN4 in the heart is, however, not confined to the sinus node cells but is found in other tissues, including cells of the conduction system. On the other hand, mutations in another cardiac ion channel gene, SCN5A, also cause sinus node dysfunction as well as other cardiac arrhythmias, including long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, and progressive cardiac conduction disturbance. These observations imply that HCN4 abnormalities may be involved in the pathogenesis of various arrhythmias, similar to the SCN5A mutations. In this study, we analyzed patients suffering from sinus node dysfunction, progressive cardiac conduction disease, and idiopathic ventricular fibrillation for mutations in HCN4. A missense mutation, D553N, was found in a patient with sinus node dysfunction who showed recurrent syncope, QT prolongation in electrocardiogram, and polymorphic ventricular tachycardia, torsade de pointes. In vitro functional study of the D553N mutation showed a reduced membranous expression associated with decreased If currents because of a trafficking defect of the HCN4 channel in a dominant-negative manner. These data suggest that the loss of function of HCN4 is associated with sinus nodal dysfunction and that a consequence of pacemaker channel abnormality might underlie clinical features of QT prolongation and polymorphic ventricular tachycardia developed under certain conditions.
authors.affiliation: Department of Molecular Pathogenesis, Medical Research Institute and Laboratory of Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ueda
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Takeharu
authors.initials: T
authors.lastname: Hayashi
authors.forename: Natsuko
authors.initials: N
authors.lastname: Inagaki
authors.forename: Megumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takuro
authors.initials: T
authors.lastname: Arimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morita
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Higashiuesato
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hirano
authors.forename: Michio
authors.initials: M
authors.lastname: Yasunami
authors.forename: Shuichi
authors.initials: S
authors.lastname: Takishita
authors.forename: Akira
authors.initials: A
authors.lastname: Yamashina
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohe
authors.forename: Makoto
authors.initials: M
authors.lastname: Sunamori
authors.forename: Masayasu
authors.initials: M
authors.lastname: Hiraoka
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D054815:Cyclic Nucleotide-Gated Cation Channels; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D020125:Mutation, Missense / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D010375:Pedigree; D015221:Potassium Channels; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D014162:Transfection
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D015221:Potassium Channels