A rare KCNE1 polymorphism, D85N, as a genetic modifier of long QT syndrome

Background The gene KCNE1 encodes the β-subunit of cardiac voltage-gated K + channels and causes long QT syndrome (LQTS). LQTS is characterized by the prolongation of QT interval and lethal arrhythmias such as torsade de pointes (TdP). A KCNE1 polymorphism, D85N, has been shown to modify the phenotype of LQTS through a loss-of-function effect on both KCNQ1 and KCNH2 channels when co-expressed and reconstituted in a heterologous expression system. Methods A screening for the D85N polymorphism was performed in 355 LQTS families with mutations in KCNQ1 , KCNH2 , or SCN5A . Among the probands who had a heterozygous status with the polymorphism, we focused on a family with a KCNH2 mutation (E58K), a N-terminal missense mutation, and examined the clinical significance of this polymorphism. We also conducted biophysical assays to analyze the effect of the polymorphism in mammalian cells. Results In 355 probands, we found 14 probands (3.9%) who had a heterozygous compound status with the D85N polymorphism. In the family with a KCNE1 -D85N polymorphism and a KCNH2 -E58K mutation, the proband and her daughter carried both the KCNH2 mutation and the KCNE1 -D85N polymorphism. They experienced repetitive syncope and TdP. Two sons of the proband had either KCNH2 -E58K mutation or KCNE1 -D85N, but were asymptomatic. Biophysical assays of KCNE1 -D85N with KCNH2 -E58K variants produced a larger reduction in the reconstituted I Kr currents compared to co-expression with wild-type KCNE1 . Conclusions The KCNE1 -D85N polymorphism modified the clinical features of LQTS patients.