| BACKGROUND Romano-Ward syndrome (RWS), an autosomal dominant trait of the hereditary long QT syndrome, is a disorder of ventricular repolarization characterized by a prolonged Q-T interval, syncope, seizures, and sudden death. Up to now, seven causative genes have been identified: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2 and Ank-B. Of these genes, the KCNQ1, which encodesαsubunit of slowly-activating delayed rectifier potassium channel (Iks) required for the repolarization phase 3 of the cardiac action potential, is considered as one of the two main causative genes. Additionally, the past studies have demonstrated that this disorder is genetically heterogeneous and can be attribute to diverse mutation in the gene.OBJECTIVES This study aims at ascertaining the molecular etiology of a Chinese family with RWS.METHOD We evaluated a family with RWS, and sequenced the candidate gene of potassium ion channel KCNQ1 after PCR amplification of genomic DNA. After identified the mutant gene, we constructed the recombinant vector which can express in the eukaryotic cells. We transfected them into the COS-7 cells for transient expression. Whole cell patch-clamp analysis was applied to detect the mutant gene functional change of related ionic channel current. Controls were 192 unrelated healthy subjects.RESULTS A heterozygous missense mutation with a G to A transition at the first position of codon 254 (GTG) was identified in 4 affected family members. As a result, valine localized within the highly conserved region known as linker between the fourth and the fifth transmembrane segments of the KCNQ1 channel is replaced by methionine (V254M). The mutation was absent in the normal individuals in the family and 192 healthy individuals. V254M significantly decreased the density of Iks current, but did not alter the kinetics.CONCLUSION The mutation (V254M) in the KCNQ1 gene exerts a dominant-negative effect on native Iks currents. The genetic defect of KCNQ1 gene is one of the molecular bases. |
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