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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., (Copyright 2009 Elsevier Inc. All rights reserved.)

Objective: Hereditary long QT syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged QT intervals and an increased risk for ventricular arrhythmias and sudden cardiac death. Mutations in the voltage-gated potassium channel subunit KCNQ1 induce the most common form of LQTS. KCNQ1 is associated with two different entities of LQTS, the autosomal-dominant Romano-Ward syndrome (RWS), and the autosomal-recessive Jervell and Lange-Nielsen syndrome (JLNS) characterized by bilateral deafness in addition to cardiac arrhythmias. In this study, we investigate and discuss dominant-negative I(Ks) current reduction by a KCNQ1 deletion mutation identified in a RWS family., Methods: Single-strand conformation polymorphism analysis and direct sequencing were used to screen LQTS genes for mutations. Mutant KCNQ1 channels were heterologously expressed in Xenopus oocytes, and potassium currents were recorded using the two-microelectrode voltage clamp technique., Results: A heterozygous deletion of three nucleotides (CTT) identified in the KCNQ1 gene caused the loss of a single phenylalanine residue at position 339 (KCNQ1-deltaF339). Electrophysiological measurements in the presence and absence of the regulatory beta-subunit KCNE1 revealed that mutant and wild type forms of an N-terminal truncated KCNQ1 subunit (isoform 2) caused much stronger dominant-negative current reduction than the mutant form of the full-length KCNQ1 subunit (isoform 1)., Conclusion: This study highlights the functional relevance of the truncated KCNQ1 splice variant (isoform 2) in establishment and mode of inheritance in long QT syndrome. In the RWS family presented here, the autosomal-dominant trait is caused by multiple dominant-negative effects provoked by heteromultimeric channels formed by wild type and mutant KCNQ1-isoforms in combination with KCNE1.