Transgenic mice overexpressing human KvLQT1 dominant-negative isoform PartI: Phenotypic characterisation

Objectives: The KCNQ1 gene encodes the KvLQT1 potassium channel, which gene rates in the human heart the slow component of the cardiac delayed rectifie r current, I-Kc. Mutations in KCNQ1 are the most frequent cause of the cong enital long QT syndrome. We have previously cloned a cardiac KCNQ1 human is oform, which exerts a strong dominant-negative effect on KvLQT1 channels. W e took advantage of this dominant-negative isoform to engineer an in vivo m odel of KvLQT1 disruption, obtained by overexpressing the dominant-negative subunit under the control of the a-myosin heavy chain promoter. Results: T hree different transgenic lines demonstrated a phenotype with increasing se verity. Functional suppression of KvLQT1 in transgenic mice led to a marked ly prolonged QT interval associated with sinus node dysfunction. Transgenic mice also demonstrated atrio-ventricular block leading to occasional Wenck ebach phenomenon. The atrio-ventricular block was associated with prolonged AH but normal HV interval in His recordings. Prolonged QT interval correla ted with prolonged action potential duration and with reduced K+ current de nsity in patch-clamp experiments. RNase protection assay revealed remodelin g of K+ channel expression in transgenic mice. Conclusions: Our transgenic mouse model suggests a role for KvLQT1 channels not only in the mouse cardi ac repolarisation but also in the sinus node automaticity and in the propag ation of the impulse through the AV node. (C) 2001 Elsevier Science B.V. Al l rights reserved.