A KCNJ8 mutation associated with early repolarization and atrial fibrillation

Abstract

Aim: The Kir 6.1 K(atp) channel is believed to play an important role in ventricular repolarization as determined from both functional and genetic studies of the potassium inwardly-rectifying channel, subfamily J, member 8 (KCNJ8)-S422L missense mutation in patients with J-wave syndromes. Although Kir6.1 is also present in atrial tissue, it is unknown whether this channel modulates atrial repolarization and hence whether the S422L mutation portends a greater risk of atrial arrhythmias. This study sought to examine whether there was an increased frequency of the KCNJ8-S422L mutation among patients with atrial fibrillation (AF) and early repolarization (ER) as a possible novel susceptibility gene for AF.

Methods and results: A total of 325 lone AF probands were identified from the Vanderbilt AF Registry, a collection of clinical data and DNA from consented, consecutively enrolled participants. The coding regions of KCNJ8 were sequenced, and the patient's presenting electrocardiogram (ECG) was reviewed by two independent physicians for ER abnormalities. The KCNJ8-S422L mutation was identified in two AF probands while no other candidate gene variants were identified in these cases. Twenty-two (7%) patients were found to have ER on the ECG, including the two probands carrying the S422L variant. In one small AF kindred, the S422L variant co-segregated with AF and ER.

Conclusions: The KCNJ8-S422L variant is associated with both increased AF susceptibility and ER indicating a role for Kir 6.1 K(atp) channel in both ventricular and atrial repolarization.

Figure 1

Proband DNA sequence chromatogram from Exon 3b of KCNJ8 with the heterozygous substitution of wild-type allele C->T at position 1265 resulting in missense mutation S422L.

Figure 2

(A) AF588 proband's electrocardiogram with both atrial fibrillation and early repolarization in the lateral leads. The arrows in leads V4–V6 indicate the leads with the highest ST-segment (segment of ECG connecting QRS complex and the T wave) elevation. (B) The proband's electrocardiogram during sinus rhythm shows early repolarization in the lateral leads. (C) The probands (AF588) father's electrocardiogram with early repolarization in the lateral leads, indicated by the arrows in lead I, AVL (augmented vector left), V5, and V6.

Figure 3

Pedigrees of families with atrial fibrillation and KCNJ8 mutations and early repolarization. Squares and circles indicate male and female members, respectively. Symbols with a slash indicate deceased family members. Arrows indicate probands. Open symbols indicate unaffected family members. Solid black symbols indicate the presence of atrial fibrillation. Half-shaded symbols indicate individuals with atrial fibrillation by history only. Small central grey squares indicate early repolarization on electrocardiogram. + symbol indicates the presence of the KCNJ8-S422L variant.