The distinct HERG missense mutation L564P causes long QT syndrome in one French Canadian family

BACKGROUND: Long QT syndrome is a congenital abnormality of cardiac repolar ization causing syncope and sudden death from ventricular tachyarrhythmias known as torsades de pointes. This hereditary cardiac disorder often shows an increase of the value of the QT interval corrected for heart rate over 0 .45 s in a 12-lead electrocardiogram. OBJECTIVE: To find and identify pertinent mutations occur ring in French Ca nadians by extracting genomic DNA from blood samples and performing a combi nation of polymerase chain reaction (PCR), single strand conformational pol ymorphism and DNA sequencing. RESULTS: A novel mutation was identified in the S5 region of the HERG potas sium channel. In codon 564 CTA, T was replaced by C, resulting in a leucine to proline substitution. Two family members had the mutation in two distin ct generations. A new restriction site was created at this position and the refore enabled the development of a rapid diagnostic test using PCR. HERG w ild type and mutant potassium channel mRNAs were then expressed in Xenopus laevis oocytes. CONCLUSION: This electrophysiological study suggests that coexpression of H ERG wild type and mutant L564P results in a dominant negative effect of the mutation.