title: Novel mechanisms of trafficking defect caused by KCNQ1 mutations found in long QT syndrome.
abstract: Long QT syndrome (LQTS) is a hereditary arrhythmia caused by mutations in genes for cardiac ion channels, including a potassium channel, KvLQT1. Inheritance of LQTS is usually autosomal-dominant, but autosomal-recessive inheritance can be observed in patients with LQTS accompanied by hearing loss. In this study, we investigated the functional alterations caused by KCNQ1 mutations, a deletion (delV595) and a frameshift (P631fs/19), which were identified in compound heterozygous state in two patients with autosomal-recessive LQTS not accompanied by hearing loss. Functional analyses showed that both mutations impaired cell surface expression due to trafficking defects. The mutations severely affected outward potassium currents without apparent dominant negative effects. It was found that delV595 impaired subunit binding, whereas P631fs/19 was retained in endoplasmic reticulum due to the newly added 19-amino acid sequence containing two retention motifs (R(633)GR and R(646)LR). This is the first report of novel mechanisms for trafficking abnormality of cardiac ion channels, providing us new insights into the molecular mechanisms of LQTS.
authors.affiliation: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8510, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Sato
authors.forename: Takuro
authors.initials: T
authors.lastname: Arimura
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.forename: Taisuke
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Aizawa
authors.forename: Hiroya
authors.initials: H
authors.lastname: Ushinohama
authors.forename: Yoshifusa
authors.initials: Y
authors.lastname: Aizawa
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D018408:Patch-Clamp Techniques; D010375:Pedigree; D016415:Sequence Alignment
chemical_list: D051657:KCNQ1 Potassium Channel