KCNQ1 gene mutations and the respective genotype-phenotype correlations in the long QT syndrome

Abstract

KCNQ1 (formerly called KVLQT1) is a Shaker-like voltage-gated potassium channel gene responsible for the LQT1 sub-type of LQTS. In general, heterozygous mutations in KCNQ1 cause Romano-Ward syndrome (LQT1 only), while homozygous mutations cause JLNS (LQT1 and deafness). To date, more than 100 families with mutations in this gene have been reported, most with their own novel 'private' mutations. The majority of these mutations are missense. However, other types of mutations, such as deletions, frame-shifts and splice-donor errors have also been reported. There is one frequently reported mutated region (the 'hot-spot'). KCNQ1 is now believed to be the most commonly mutated gene in LQTS. The combination of normal and mutant KCNQ1 alpha-subunits has been found to form abnormal IKS channels, hence mutations associated with the KCNQ1 gene are also believed to act mainly through a dominant-negative mechanism (the mutant form interferes with the function of the normal wild-type form through a 'poison pill' type mechanism) or loss of function mechanism. Even in the case of carriers of the same mutation, it is currently unknown why there are significant clinical phenotype variations in LQT1 patients. This question could be answered by increasing the number of patient genotypes studied. LQT1 patients experience a majority of their cardiac events (62%) during exercise, and only 3% occur during rest or sleep. Of the patients who experienced cardiac events while swimming, 99% were LQT1. Auditory stimuli are rare and occur in only 2% of patients. However, both lethal and non-lethal events follow the same pattern.