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.