title: Biophysical characterization of KCNQ1 P320 mutations linked to long QT syndrome 1.
abstract: Hereditary long QT syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on the surface ECG and a high risk for arrhythmia-related sudden death. Mutations in a cardiac voltage-gated potassium channel, KCNQ1, account for the most common form of LQTS, LQTS1. The objective of this study was the characterization of a novel KCNQ1 mutation linked to LQTS. Electrophysiological properties and clinical features were determined and compared to characteristics of a different mutation at the same position. Single-strand conformation polymorphism analysis followed by direct sequencing was performed to screen LQTS genes for mutations. A novel missense mutation in the KCNQ1 gene, KCNQ1 P320H, was identified in the index patient presenting with recurrent syncope and aborted sudden death triggered by physical stress and swimming. Electrophysiological analyses of KCNQ1 P320H and the previously reported KCNQ1 P320A mutation indicate that both channels are non-functional and suppress wild type I(Ks) in a dominant-negative fashion. Based on homology modeling of the KCNQ1 channel pore region, we speculate that the proline residue at position 320 limits flexibility of the outer pore and is required to maintain the functional architecture of the selectivity filter/pore helix arrangement. Our observations on the KCNQ1 P320H mutation are consistent with previous studies indicating that pore mutations in potassium channel alpha-subunits are associated with more severe electrophysiological and clinical phenotypes than mutations in other regions of these proteins. This study emphasizes the significance of mutation screening for diagnosis, risk-assessment, and mutation-site specific management in LQTS patients.
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. dthomas@ix.urz.uni-heidelberg.de
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Markus
authors.initials: M
authors.lastname: Khalil
authors.forename: Markus
authors.initials: M
authors.lastname: Alter
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Schweizer
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Karle
authors.forename: Anna-Britt
authors.initials: AB
authors.lastname: Wimmer
authors.forename: Manuela
authors.initials: M
authors.lastname: Licka
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Michael
authors.initials: M
authors.lastname: Koenen
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Ulmer
authors.forename: Jörg
authors.initials: J
authors.lastname: Zehelein
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D004594:Electrophysiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009154:Mutation; D010375:Pedigree; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D029597:Romano-Ward Syndrome / Q000235:genetics*
chemical_list: C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated