Screening for mutations and polymorphisms in the genes KCNH2 and KCNE2 encoding the cardiac HERG/MiRPI ion channel: Implications for acquired and congenital long Q-T syndrome

Background: The voltage-gated, rapid-delayed rectifier current (I-Kr) is im portant for repolarization of the heart, and mutations in the genes coding for the K+-ion channel conducting this current, i.e., KCNH2 for the alpha - subunit HERG and KCNE2 for the beta -subunit MiRP1, cause acquired and cong enital long Q-T syndrome (LQTS) and other cardiac arrhythmias. Methods: We developed a robust single-strand conformation polymorphism-hete roduplex screening analysis, with identical thermocycling conditions for al l PCR reactions, covering all of the coding exons in KCNH2 and KCNE2. The m ethod was used to screen 40 unrelated LQTS patients. Results: Eleven mutations, of which six were novel, were found in KCNH2. In terestingly, six mutations were found in the region of the gene coding for the Per-Arnt-Sim (PAS) and PAS-S1 regions of the HERG protein, stressing th e need to examine the entire gene when screening for mutations. No mutation s were found in KCNE2, suggesting that direct involvement of MiRP1 in LQTS is rare. Furthermore, four novel single-nucleotide polymorphisms (SNPs) and one amino acid polymorphism (R1047L) were identified in KCNH2, and one nov el SNP and one previously known amino acid polymorphism (T8A) were found in KCNE2. Conclusions: The potential role of rare polymorphisms in the HERG/MiRP1 K+- channel should be clarified with respect to drug interactions and susceptib ility to arrhythmia and sudden death. (C) 2001 American Association for Cli nical Chemistry.