The R231C KCNQI Mutation Causes Familial Atrial Fibrillation and Long QT Syndrome

Daniel C Bartos andd Brian P Delisle, University of Kentucky, Lexington, KY; Sabine Duchatelet, Veronique Fressart, and Pascale Guicheney, Pitie-Salpetriere Hopital, Paris, France; Didler Klug, Hopital Cardiologique de Lille, Lille, France; Jean-Marc Lupoglazoff, Hopital Robert-Debre, Paris, France; Isabelle Denjoy, Hopital Laribolslere, Paris, France; and Craig T January, University of Wisconsin-Madison, Madison, WI

This poster presentation, part of the "Ion Channels and Cardiac Rhythm" abstract poster session, reviewed the results of study that Bartos and colleagues conducted in order to determine the mutation behind the development of familial atrial fibrillation (FAF2 and long QT syndromes (LQT1).

With the knowledge that "KCNQ1 encodes a voltage-gated K⁺ channel a-subunit that underlies the slowly activating delayed rectifier K⁺ current... in the heart, and KCNQ1 mutations cause long and short QT syndromes" and FAF2," as well as and understanding that "KCNQ1 mutations causing LQT typically result in a loss-of-function, whereas KCNQ1 mutations associated with FAF2 or SQT2 induce a gain-of-funciton," the researchers identified a "heterozygous R231-C- KCNQ1 missense mutation in six families." One mutation was with FAF2 and the other five with LQT1, with most carries in the LQT1 family asymptomatic.

The team expressed the auxillary K⁺ channel subunit KCNE1 and WT-KCNQ1, R231C-KCNQ1, or WT- and R231C-KCNQ1 cDNA in HEK293 cells in order to better understand the functional phenotype of R231C. Measurements of KCNQ1 current were performed by pulsing cells from -80 to 70 mV in 10-mV increments followed by a pulse to -50 mV.

They found that cells expressing "WT-KCNQ1/KCNE1 generated ^IKCNQ1 similar to ^IKs (n=34 cells); cells expressing R231C-KCNQ1/KCNE1 generated a gain-of-function phenotype and exhibited very large ^IKCNQ1 that was constitutively active at all membrane potentials tested (n=13 cells); and cells expressing WT-KCNQ1/R231C-KCNQ1/KCNE1 resulted in a mixed ^IKCNQ1 phenotype with voltage-dependent and constitutively active components (n=22 cells). Compared to cells expressing WT-KCNQ1/KCNE1, cells expressing WT-KCNQ1/R231C-KCNQ1/KCNE1 had larger ^IKCNQ1 at positive membrane potentials ≤ 0 mV (p<0.05) but smaller ^IKCNQ1 at membrane potentials ≥ 40 mV (p<0.05). The ^IKCNQ1 at negative membrane potentials resembled a gain-of-function phenotype similar to the FAF2 mutations S140G and V14M, however, the reduction of ^IKCNQ1 at positive membrane potentials mimicked the loss-of-function phenotype associated with LQT1 mutations. These unique functional characteristics may explain the mild and variable QT prolongation detected in most of the R231C carriers and the occurrence of FAF2 or LQT1 in different families."

The researchers concluded that although "additional unknown factors may contribute to the phenotype variability, this study demonstrates that a single mutation is linked to FAF2 and LQT1."