A novel long-QT 5 gene mutation in the C-terminus (V109I) is associated with a mild phenotype

Abstract

Mutations in the human minK gene KCNE1 have been linked to autosomal dominant and autosomal recessive long-QT (LQT) syndrome, a cardiac condition predisposing to ventricular arrhythmias. minK and K_vLQT1, the LQT1 gene product, form a native cardiac K⁺ channel that regulates the slowly delayed rectifier potassium current I_Ks. We used single-strand conformation polymorphism and sequencing techniques to identify novel KCNE1 mutations in patients with a congenital LQT syndrome of unknown genetic origin. In 150 unrelated index patients a missense mutation (V109I) was identified that significantly reduced the wild-type I_Ks current amplitude (by 36%) when coexpressed with K_vLQT1 in Xenopus oocytes. Other biophysical properties of the I_Ks channel were not altered. Since we observed incomplete penetrance (only one of two mutation carriers could be diagnosed by clinical criteria), and the family's history was unremarkable for sudden cardiac death, the 109I allele most likely causes a mild phenotype. This finding may have implications for the occurrence of "acquired" conditions for ventricular arrhythmias and thereby the potential cardiac risk for asymptomatic mutation carriers still remains to be determined.