OBJECTIVE: Hereditary long QT syndrome (LQTS) is a genetically heterogeneous 
disease characterized by prolonged QT intervals and an increased risk for 
ventricular arrhythmias and sudden cardiac death. Mutations in the voltage-gated 
potassium channel subunit KCNQ1 induce the most common form of LQTS. KCNQ1 is 
associated with two different entities of LQTS, the autosomal-dominant 
Romano-Ward syndrome (RWS), and the autosomal-recessive Jervell and 
Lange-Nielsen syndrome (JLNS) characterized by bilateral deafness in addition to 
cardiac arrhythmias. In this study, we investigate and discuss dominant-negative 
I(Ks) current reduction by a KCNQ1 deletion mutation identified in a RWS family.
METHODS: Single-strand conformation polymorphism analysis and direct sequencing 
were used to screen LQTS genes for mutations. Mutant KCNQ1 channels were 
heterologously expressed in Xenopus oocytes, and potassium currents were 
recorded using the two-microelectrode voltage clamp technique.
RESULTS: A heterozygous deletion of three nucleotides (CTT) identified in the 
KCNQ1 gene caused the loss of a single phenylalanine residue at position 339 
(KCNQ1-deltaF339). Electrophysiological measurements in the presence and absence 
of the regulatory beta-subunit KCNE1 revealed that mutant and wild type forms of 
an N-terminal truncated KCNQ1 subunit (isoform 2) caused much stronger 
dominant-negative current reduction than the mutant form of the full-length 
KCNQ1 subunit (isoform 1).
CONCLUSION: This study highlights the functional relevance of the truncated 
KCNQ1 splice variant (isoform 2) in establishment and mode of inheritance in 
long QT syndrome. In the RWS family presented here, the autosomal-dominant trait 
is caused by multiple dominant-negative effects provoked by heteromultimeric 
channels formed by wild type and mutant KCNQ1-isoforms in combination with 
KCNE1.