TY - JOUR

T1 - Genetic variation in KCNA5

T2 - impact on the atrial-specific potassium current IKur in patients with lone atrial fibrillation

AU - Christophersen, Ingrid E

AU - Olesen, Morten S

AU - Liang, Bo

AU - Andersen, Martin N

AU - Larsen, Anders P

AU - Nielsen, Jonas Bøje

AU - Haunsø, Stig

AU - Olesen, Søren-Peter

AU - Tveit, Arnljot

AU - Svendsen, Jesper H

AU - Schmitt, Nicole

PY - 2012/12/21

Y1 - 2012/12/21

N2 - AimsGenetic factors may be important in the development of atrial fibrillation (AF) in the young. KCNA5 encodes the potassium channel a-subunit K(V)1.5, which underlies the voltage-gated atrial-specific potassium current I(Kur). KCNAB2 encodes K(V)ß2, a ß-subunit of K(V)1.5, which increases I(Kur). Three studies have identified loss-of-function mutations in KCNA5 in patients with idiopathic AF. We hypothesized that early-onset lone AF is associated with high prevalence of genetic variants in KCNA5 and KCNAB2.Methods and resultsThe coding sequences of KCNA5 and KCNAB2 were sequenced in 307 patients with mean age of 33 years at the onset of lone AF, and in 216 healthy controls. We identified six novel non-synonymous mutations [E48G, Y155C, A305T (twice), D322H, D469E, and P488S] in KCNA5 in seven patients. None were present in controls. We identified a significantly higher frequency of rare deleterious variants in KCNA5 in the patients than in controls. The mutations were analysed with confocal microscopy and whole-cell patch-clamp techniques. The mutant proteins Y155C, D469E, and P488S displayed decreased surface expression and loss-of-function in patch-clamp studies, whereas E48G, A305T, and D322H showed preserved surface expression and gain-of-function for K(V)1.5.ConclusionThis study is the first to present gain-of-function mutations in KCNA5 in patients with early-onset lone AF. We identified three gain-of-function and three loss-of-function mutations. We report a high prevalence of variants in KCNA5 in these patients. This supports the hypothesis that both increased and decreased potassium currents enhance AF susceptibility.

AB - AimsGenetic factors may be important in the development of atrial fibrillation (AF) in the young. KCNA5 encodes the potassium channel a-subunit K(V)1.5, which underlies the voltage-gated atrial-specific potassium current I(Kur). KCNAB2 encodes K(V)ß2, a ß-subunit of K(V)1.5, which increases I(Kur). Three studies have identified loss-of-function mutations in KCNA5 in patients with idiopathic AF. We hypothesized that early-onset lone AF is associated with high prevalence of genetic variants in KCNA5 and KCNAB2.Methods and resultsThe coding sequences of KCNA5 and KCNAB2 were sequenced in 307 patients with mean age of 33 years at the onset of lone AF, and in 216 healthy controls. We identified six novel non-synonymous mutations [E48G, Y155C, A305T (twice), D322H, D469E, and P488S] in KCNA5 in seven patients. None were present in controls. We identified a significantly higher frequency of rare deleterious variants in KCNA5 in the patients than in controls. The mutations were analysed with confocal microscopy and whole-cell patch-clamp techniques. The mutant proteins Y155C, D469E, and P488S displayed decreased surface expression and loss-of-function in patch-clamp studies, whereas E48G, A305T, and D322H showed preserved surface expression and gain-of-function for K(V)1.5.ConclusionThis study is the first to present gain-of-function mutations in KCNA5 in patients with early-onset lone AF. We identified three gain-of-function and three loss-of-function mutations. We report a high prevalence of variants in KCNA5 in these patients. This supports the hypothesis that both increased and decreased potassium currents enhance AF susceptibility.

U2 - 10.1093/eurheartj/ehs442

DO - 10.1093/eurheartj/ehs442

M3 - Journal article

C2 - 23264583

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

ER -