The Connexin40A96S mutation from a patient with atrial fibrillation causes decreased atrial conduction velocities and sustained episodes of induced atrial fibrillation in mice.
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and a major cause of stroke. In the mammalian heart the gap junction proteins connexin40 (Cx40) and connexin43 (Cx43) are strongly expressed in the atrial myocardium mediating effective propagation of electrical impulses. Different heterozygous mutations in the coding region for Cx40 were identified in patients with AF. We have generated transgenic Cx40A96S mice harboring one of these mutations, the loss-of-function Cx40A96S mutation, as a model for atrial fibrillation. Cx40A96S mice were characterized by immunochemical and electrophysiological analyses. Significantly reduced atrial conduction velocities and strongly prolonged episodes of atrial fibrillation were found after induction in Cx40A96S mice. Analyses of the gating properties of Cx40A96S channels in cultured HeLa cells also revealed significantly lower junctional conductance and enhanced sensitivity voltage gating of Cx40A96S in comparison to Cx40 wild-type gap junctions. This is caused by reduced open probabilities of Cx40A96S gap junction channels, while single channel conductance remained the same. Similar to the corresponding patient, heterozygous Cx40A96S mice revealed normal expression levels and localization of the Cx40 protein. We conclude that heterozygous Cx40A96S mice exhibit prolonged episodes of induced atrial fibrillation and severely reduced atrial conduction velocities similar to the corresponding human patient.
Life and Medical Sciences (LIMES) Institute, Molecular Genetics, University of Bonn, Bonn, Germany.
Indra
I
Lübkemeier
René
R
Andrié
Lars
L
Lickfett
Felicitas
F
Bosen
Florian
F
Stöckigt
Radoslaw
R
Dobrowolski
Astrid M
AM
Draffehn
Julien
J
Fregeac
Joachim L
JL
Schultze
Feliksas F
FF
Bukauskas
Jan Wilko
JW
Schrickel
Klaus
K
Willecke
D000818:Animals; D001281:Atrial Fibrillation / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D004562:Electrocardiography; D004719:Endomyocardial Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D056149:Epicardial Mapping; D017629:Gap Junctions / Q000235:genetics; D006367:HeLa Cells; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D013997:Time Factors; D014162:Transfection; D014463:Ultrasonography; D000097003:Gap Junction alpha-5 Protein
D018031:Connexin 43; D017630:Connexins; D000097003:Gap Junction alpha-5 Protein; C082920:connexin 45
AF; ARP; AV-nodal refractory period; AVNRP; Atrial fibrillation; CV; Connexin40; Cx; Cx40A96S; EAM; ECG; ED; EPI; GJ; Gap junctions; PD; SAECG; VRP; WBP; Wenckebach periodicity; atrial fibrillation; atrial refractory period; conduction velocity; connexin; electrocardiogram; electrophysiological investigation; embryonic day; epicardial activation mapping; g(j); gap junction; junctional conductance; mutation in the connexin40 sequence that leads to the exchange of amino acid residue alanine with serine at position 96 of the Cx40 peptide sequence; postnatal day; standard average ECG recording; ventricular refractory period