A Double‐Point Mutation in the Selectivity Filter Site of the KCNQ1 Potassium Channel Results in a Severe Phenotype, LQT1, of Long QT Syndrome

INTRODUCTION: Slowly activating delayed-rectifier potassium currents in the heart are produced by a complex protein with alpha and beta subunits composed of the potassium voltage-gated channel KQT-like subfamily, member 1 (KCNQ1) and the potassium voltage-gated channel Isk-related family, member 1 (KCNE1), respectively. Mutations in KCNQ1 underlie the most common type of hereditary long QT syndrome (LQTS). Like other potassium channels, KCNQ1 has six transmembrane domains and a highly conserved potassium selectivity filter in the pore helix called "the signature sequence." We aimed to investigate the functional consequences of a newly identified mutation within the signature sequence. METHODS AND RESULTS: Potassium channel genomic DNA from a family with clinical evidence of LQTS was amplified by polymerase chain reaction (PCR), and the resulting products were then sequenced. Three family members had a double-point mutation in KCNQ1 at nucleotides 938 (T-to-A) and 939 (C-to-A), resulting in an isoleucine-to-lysine change at amino acid position 313. These patients displayed prolonged QTc intervals (629, 508, and 500 ms(1/2,) respectively) and repetitive episodes of syncope, but no deafness. Three-dimensional structure modeling of KCNQ1 revealed that this mutation is located at the center of the channel pore. COS-7 cells displayed a lack of current when transfected with a plasmid expressing the mutant. In addition, the mutant displayed a dominant negative effect on current but appeared normal with respect to plasma membrane integration. CONCLUSION: An I313K mutation within the selectivity filter of KCNQ1 results in a dominant-negative loss of channel function, leading to a long QT interval and subsequent syncope.