title: A KCNQ1 mutation causes age-dependant bradycardia and persistent atrial fibrillation.
abstract: Atrial fibrillation (AF) is the most common arrhythmia. Gain-of-function mutations in KCNQ1, the pore-forming α-subunit of the slow delayed rectifier K current (IKs) channel, have been associated with AF. The purpose of this study was functional assessment of a mutation in KCNQ1 identified in a family with persistent AF and sinus bradycardia. We investigated whether this KCNQ1 missense mutation could form the genetic basis for AF and bradycardia simultaneously in this family. Sanger sequencing in a family with hereditary persistent AF identified a novel KCNQ1 variant (V241F) in a highly conserved region of S4 domain. The proband and her son developed bradycardia and persistent AF in an age-dependent fashion. The other son was a mutation carrier but he showed sinus bradycardia and not AF. Whole-cell patch clamp electrophysiology showed that V241F mutation in KCNQ1 shifted the activation curve to the left and dramatically slowed deactivation, leading to a constitutively open-like phenotype. Computer modeling showed that V241F would slow pacemaker activity. Also, simulations of atrial excitation predicted that V241F results in extreme shortening of action potential duration, possibly resulting in AF. Our study indicates that V241F might cause sinus bradycardia by increasing IKs. Additionally, V241F likely shortens atrial refractoriness to promote a substrate for reentry. KCNQ1 mutations have previously been described in AF, yet this is the first time a mutation in KCNQ1 is associated with age-dependent bradycardia and persistent AF. This finding further supports the hypothesis that sinus node dysfunction contributes to the development of AF.
authors.affiliation: Departments of Laboratory Medicine and Genetics, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Chang-Seok
authors.initials: CS
authors.lastname: Ki
authors.forename: Chae Lim
authors.initials: CL
authors.lastname: Jung
authors.forename: Hyun-ji
authors.initials: HJ
authors.lastname: Kim
authors.forename: Kwan-Hyuck
authors.initials: KH
authors.lastname: Baek
authors.forename: Seung Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Young Keun
authors.initials: YK
authors.lastname: On
authors.forename: Ki-Suk
authors.initials: KS
authors.lastname: Kim
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Noh
authors.forename: Jae Boum
authors.initials: JB
authors.lastname: Youm
authors.forename: June Soo
authors.initials: JS
authors.lastname: Kim
authors.forename: Hana
authors.initials: H
authors.lastname: Cho
mesh_terms: D000200:Action Potentials; D000328:Adult; D000367:Age Factors; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology*; D001919:Bradycardia / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human