A Kir2.1 Mutation Underlies Familial Atrial Fibrillation

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia. Itsprevalence is 0.4% in the general population, increasing with age up to 6% in thoseabove 60 years of age. AF causes a 2-fold increase in mortality and a 2-to 6-foldincrease in risk for stroke. To date, the mechanisms of AF are poorly known. About36% patients with AF had no evident pathogeny, and 5% had a positive family history.Familial atrial fibrillation (FAF) is a genetic rhythm disorder characterized byearly-onset AF and autosomal dominant inheritance. In 2003, we first reported anS140G missense mutation of KCNQ1, an a subunit of potassium, in one Chinesekindred with AF. Functional analysis of the mutation revealed a gain-of-functionconsequence on both KCNQ1-KCNE1 and KCNQ1-KCNE2 channels. In 2004, weidentified an R-to-C mutation at position 27 of KCNE2, aβsubunit of potassium, intwo Chinese kindreds with AF by candidate genes screening. Similarly, theelectrophysiological studies revealed a gain-of-function effect on the conductance ofKCNQ1-KCNE2 channel. The two mutations were present in all affected members inthe kindreds and were absent in hundreds of healthy unrelated Chinese subjects.Moreover, familial AF was also linked to the loci of chromosome 10q22-24,chromosome 6q14-16 and chromosome 5p13 in some patients. Therefore, familial AFis genetically heterogeneous. The molecular and genetic basis for the disorder in mostpatients remains to be further investigated.Objectives The aim of this study was to identify causative or related genes offamilial AF and elucidate the molecular genetics mechanism of AF. Methods We evaluated 30 unrelated kindreds with familial AF, and sequenced 10candidate genes of ion channels or transporter related genes KCNQ1,HERG,SCN5A,ANK-B,KCNE1,KCNE2,KCNE3,KCNE4,KCNE5 and KCNJ2 after PCRamplification of genomic DNA. After having found the mutant gene, we constructedthe recombinant vectors expressed in the eukaryotic cells. We transfected them intothe tool cells COS-7 and HEK-293 for transient expression. Whole-cell patch-clampanalysis was performed to detect the functional change of related ionic channelcurrent in mutant. Controls were 420 healthy subjects.Results Of the 30 probands, one had a valine-to-isoleucine mutation at position93 of KCNJ2. The same mutation was found in all of the affected members in thekindred, but absent in 420 healthy subjects. The protein sequence alignment showedthat the sequence flanking the KCNJ2 mutation was highly conserved. Theelectrophysiological studies demonstrated that the V93I mutant had again-of-function effect on the Kir2.1 current.Conclusions The potassium channel Kir2.1V93I mutation may play a role ininitiating and/or maintaining AF by increasing the activity of inward rectifierpotassium channel. Increase of I_K1-like currents may be a general mechanism forAF.