A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly

The LQT1 locus (KCNQ1) has been correlated with the most common form of inh erited long QT (LQT) syndrome. LQT patients suffer from syncopal episodes a nd high risk of sudden death. The KCNQ1 gene encodes KvLQT1 alpha-subunits, which together with auxiliary IsK (KCNE1, minK) subunits form IKs K+ chann els, Mutant KvLQT1 subunits may be associated either with an autosomal domi nant form of inherited LQT, Romano-Ward syndrome, or an autosomal recessive form, Jervell and Lange-Nielsen syndrome (JLNS). We have identified a smal l domain between residues 589 and 620 in the KvLQT1 C-terminus, which may f unction as an assembly domain for KvLQT1 subunits, KvLQT1 C-termini do not assemble and KvLQT1 subunits do not express functional K+ channels without this domain. We showed that a JLN deletion-insertion mutation at KvLQT1 res idue 544 eliminates important parts of the C-terminal assembly domain. Ther efore, JLN mutants may be defective in KvLQT1 subunit assembly, The results pro,ide a molecular basis for the clinical observation that heterozygous J LN carriers show slight cardiac dysfunctions and that the severe JLNS pheno type is characterized by the absence of KvLQT1 channel.