PROPERTIES OF KVLQT1 K-WARD AND JERVELL AND LANGE-NIELSEN INHERITED CARDIAC-ARRHYTHMIAS( CHANNEL MUTATIONS IN ROMANO)

Mutations in the delayed rectifier K+ channel subunit KvLQT1 have been identified as responsible for both Romano-Ward (RW) and Jervell and L ange-Nielsen (JLN) inherited long QT syndromes, We report the molecula r cloning of a human KvLQT1 isoform that is expressed in several human tissues including heart, Expression studies revealed that the associa tion of KvLQT1 with another subunit, IsK, reconstitutes a channel resp onsible for the I-Ks current involved in ventricular myocyte repolariz ation, Six RW and two JLN mutated KvLQT1 subunits were produced and co -expressed with IsK in COS cells, All the mutants? except R555C, fail to produce functional homomeric channels and reduce the K+ current whe n co-expressed with the wild-type subunit. Thus, in both syndromes, th e main effect of the mutations is a dominant-negative suppression of K vLQT1 function, The JLN mutations have a smaller dominant-negative eff ect, in agreement viith the fact that the disease is recessive, The R5 55C subunit forms a functional channel when expressed with IsK, but wi th altered gating properties, The voltage dependence of the activation is strongly shifted to more positive values, and deactivation kinetic s are accelerated, This finding indicates the functional importance of a small positively charged cytoplasmic region of the KvLQT structure where two RW and one JLN mutations have been found to take place.