Novel mutations in KvLQT1 that affect I-ks activation through interactionswith Isk

Objectives: We report the functional expression of four KCNQ1 mutations aff ecting arginine residues and resulting in Romano-Ward (RW) and the Jervell and Lange-Nielsen (JLN) congenital long QT syndromes. Results: The R539W an d R190Q mutations were found in typical RW families with an autosomal domin ant transmission. The R243H mutation was found in a compound heterozygous J LN patient who presents with deafness and cardiac symptoms. The fourth muta tion, R533W, was a new case of recessive form of the RW syndrome since homo zygous carriers experienced syncopes but showed no deafness, whereas the he terozygous carriers were asymptomatic. The R190Q mutation failed to produce functional homomeric channels. The R243H, R533W and R539W mutations induce d a positive voltage shift of the channel activation but only when co-expre ssed with IsK, pointing out the critical role of these positively charged r esidues in the modulation of the gating properties of KvLQT1 by IsK. The po sitive shift induced by R533W was merely 15%. This small effect was compati ble with the recessive character of the RW phenotype transmission. The aver age QTc was significantly longer (P<0.01) in patients carrying mutations in ducing a total loss of channel function and those patients were also prone to cardiac adverse symptoms (whether syncopes or sudden death) to a greater extent (62 vs. 21%, P<0.001). Conclusions: Novel mutations are described t hat induce a voltage shift of the channel activation only in the presence o f IsK. They appear associated with a milder cardiac phenotype. (C) 2000 Els evier Science B.V. All rights reserved.