Effect of the antimalarial drug halofantrine in the long QT syndrome due to a mutation of the cardiac sodium channel gene SCN5A

T congenital long QT syndrome (LQTS) is characterized by prolongation of the QT interval as a consequence of a repolarization defect, risk of ventricular tachyarrhythmias (e.g., torsades de pointes), syncopal attacks, and sudden death.1 A variety of pharmacologic agents that delay ventricular repolarization by blocking the HERG channel responsible for the rapid component of the delayed rectifier potassium current IKr may increase the QT interval duration. The most prevalent forms of inherited LQTS are caused by mutated potassium channels KCNQ1 (type LQT1) or HERG (type LQT2), whereas mutations of the sodium channel SCN5A (type LQT3) as well as potassium channel beta-subunits minK (type LQT5) and MiRP (type LQT6) are rare causes of the syndrome.2 Mutations of SCN5A that lead to its inadequate inactivation result in the LQT3 phenotype.3 We describe here the first disease-causing mutation thus far localized in the S5 segment of the fourth SCN5A channel domain. In 2 of the mutation carriers, therapy with the antimalarial drug halofantrine induced a marked prolongation of the QTc interval and torsades de pointes, demonstrating that specific drug treatment may induce ventricular tachycardia in LQT3. • • • The present study represents an extension of our previous investigations in which we have been able to identify 6 different KCNQ14 (and unpublished observations) and 9 different HERG5,6 mutations in 60 Finnish LQTS families. In the present study, 30 unrelated Finnish probands with an autosomal dominant form of LQTS and with a hitherto undefined mutational background were examined. All of them had QTc values of .440 ms, were symptomatic, and had normal hearing. Genomic DNA was isolated from venous blood using standard methods. All patients gave their consent to the study, which was approved by the Ethical Review Committee of the Department of Medicine, University of Helsinki. Because the previously reported mutations appear to cluster in exons 23, 26, and 28 of the SCN5A gene,2 these exons were selected as targets for initial screening. The exon sequences were amplified by polymerase chain reaction using primers described previously7 and sequenced automatically as also previously described.6 Because of the large size of exon 28, only the first 725 N-terminal nucleotides, including transmembrane domains, were studied. Comparison of the SCN5A sequence to its homologs was performed using the BLAST2 sequence alignment program (http:// www.ncbi.nlm.nih.gov/gorf/wblast2.cgi). Student’s t test was used to compare mean QTc values. A nucleotide transition G4999A, predicted to substitute isoleucine (I) for valine (V) at codon 1667, was detected in 1 of the probands. The V1667I mutation is located in exon 28 of the SCN5A gene, corresponding to the highly conserved aminoterminal part of the IV/S5 domain of the sodium channel. The occurrence of the V1667I mutation was studied in the available family members of the proband and was found to be present in heterozygous form in 8 additional subjects (Figure 1), whereas it was absent in 6 remaining family members and in 50 healthy unrelated controls. The mean QTc interval of the V1667I carriers (450 6 30 ms) was significantly longer than that of noncarriers of the family (Figure 1). No mutations have been found in the KCNQ1, HERG, minK, or MiRP genes in this family. Two of 9 mutation carriers were symptomatic, with symptoms triggered by drug administration. The proband, a 16-year old male, had clinically established LQTS based on a history of syncope and prolonged QT interval, whereas his 40-year old mother had previously been asymptomatic. Clinical data of these 2 individuals have been previously reported.8 Both paFrom the Department of Medicine and Hospital for Children and Adolescents, Helsinki University Hospital, Helsinki, Finland. This study was supported by research grants from the Council for the Health Sciences of the Academy of Finland, the Sigrid Juselius Foundation, and the Finnish Foundation for Cardiovascular Research, Helsinki, Finland; the Research and Science Foundation of Farmos, Espoo, Finland; and the Emil Aaltonen Foundation, Tampere, Finland. Dr. Kontula’s address is: Department of Medicine, University of Helsinki, Haartmaninkatu 4, 00290 Helsinki, Finland. E-mail: Kimmo. Kontula@hus.fi. Manuscript received July 19, 2000; revised manuscript received and accepted October 16, 2000. FIGURE 1. Pedigree of the LQT3 family. Empty circles and/or squares: unaffected women and/or men; filled circles and/or squares: affected women and/or men. Subjects marked by an arrow had halofantrine-induced torsades de pointes. Corrected QT intervals (QTc in milliseconds), when available, are shown under individual symbol. Neither clinical nor genetic data were available from those labeled with a question mark.