Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. We first reported an S140G mutation of KCNQ1, an alpha subunit of potassium channels, in one Chinese kindred with AF. However, the molecular defects and cellular mechanisms in most patients with AF remain to be identified. We evaluated 28 unrelated Chinese kindreds with AF and sequenced eight genes of potassium channels (KCNQ1, HERG, KCNE1, KCNE2, KCNE3, KCNE4, KCNE5, and KCNJ2). An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the beta subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current, was found in 2 of the 28 probands. The mutation was present in all affected members in the two kindreds and was absent in 462 healthy unrelated Chinese subjects. Similar to KCNQ1 S140G, the mutation had a gain-of-function effect on the KCNQ1-KCNE2 channel; unlike long QT syndrome-associated KCNE2 mutations, it did not alter HERG-KCNE2 current. The mutation did not alter the functions of the HCN channel family either. Thus, KCNE2 R27C is a gain-of-function mutation associated with the initiation and/or maintenance of AF.

Figure 1

KCNE2 R27C mutation associated with AF. A, Pedigrees of families 1 and 2. Squares indicate male family members; circles, female family members; symbols with a slash, members who had died; blackened symbols, affected members; unblackened symbols, unaffected members; and arrows, probands. Asterisks indicate mutation carriers who had premature atrial complexes. II-1 and II-5 in family 1 and II-3 and II-6 in family 2 had apparent recurrent palpitation. B, Standard 12-lead electrocardiogram of an affected member (II-1 in family 2). C, Sequence analysis of DNA from the affected family members, after PCR amplification revealed a C→T substitution at nucleotide 79 in KCNE2 causing an R27C mutation in families 1 and 2.

Figure 2

Gain-of-function effect of the KCNE2 R27C mutation. A–C, Representative whole-cell current traces. These were recorded from COS-7 cells transfected with KCNQ1 alone (A), cells cotransfected with KCNQ1 and KCNE2 (B), and cells cotransfected with KCNQ1 and KCNE2 R27C (C). D, Plot of current density versus voltage for cotransfection of KCNQ1 and KCNE2 (▴) (n = 30) or for cotransfection of KCNQ1 and KCNE2 R27C (▪) (n=26) at room temperature. E, Comparison of current density at −110 mV (inward current) and +30 mV (outward current) at room temperature. Q1-T8A represents cells cotransfected with KCNQ1 and KCNE2 T8A (n=15); Q1-Q9E, cells cotransfected with KCNQ1 and KCNE2 Q9E (n=14); Q1-E2, cells cotransfected with KCNQ1 and KCNE2 (n=30); and Q1-R27C, cells cotransfected with KCNQ1 and KCNE2 R27C (n=26). Cells were held at −80 mV before depolarization to various test potentials from −120 mV to +60 mV in 10-mV increments for 2,000 ms and then were held at −40 mV for 500 ms.