title: Probucol aggravates long QT syndrome associated with a novel missense mutation M124T in the N-terminus of HERG.
abstract: Patients with LQTS (long QT syndrome) with a mutation in a cardiac ion channel gene, leading to mild-to-moderate channel dysfunction, may manifest marked QT prolongation or torsade de pointes only upon an additional stressor. A 59-year-old woman had marked QT prolongation and repeated torsade de pointes 3 months after initiation of probucol, a cholesterol-lowering drug. We identified a single base substitution in the HERG gene by genetic analysis. This novel missense mutation is predicted to cause an amino acid substitution of Met(124)-->Thr (M124T) in the N-terminus. Three other relatives with this mutation also had QT prolongation and one of them had a prolonged QT interval and torsade de pointes accompanied by syncope after taking probucol. We expressed wild-type HERG and HERG with M124T in Xenopus oocytes and characterized the electrophysiological properties of these HERG channels and the action of probucol on the channels. Injection of the M124T mutant cRNA into Xenopus oocytes resulted in expression of functional channels with markedly smaller amplitude. In both HERG channels, probucol decreased the amplitude of the HERG tail current, decelerated the rate of channel activation, accelerated the rate of channel deactivation and shifted the reversal potential to a more positive value. The electrophysiological study indicated that QT lengthening and cardiac arrhythmia in the two present patients were due to inhibition of I(Kr) (rapidly activating delayed rectifier K(+) current) by probucol, in addition to the significant suppression of HERG current in HERG channels with the M124T mutation.
authors.affiliation: Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. kenshi@yd6.so-net.ne.jp
authors.forename: Kenshi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Masami
authors.initials: M
authors.lastname: Shimizu
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ino
authors.forename: Masato
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Terai
authors.forename: Naoto
authors.initials: N
authors.lastname: Hoshi
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Higashida
authors.forename: Nariaki
authors.initials: N
authors.lastname: Terashima
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Uno
authors.forename: Honin
authors.initials: H
authors.lastname: Kanaya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000009:adverse effects*; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005192:Family Health; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008564:Membrane Potentials / Q000502:physiology; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D011341:Probucol / Q000009:adverse effects*; D012313:RNA / Q000235:genetics; D000079962:RNA, Circular; D016171:Torsades de Pointes / Q000235:genetics / Q000503:physiopathology; D014981:Xenopus
chemical_list: D000924:Anticholesteremic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D000079962:RNA, Circular; D012313:RNA; D011341:Probucol