title: Electrophysiologic consequences of KATP gain of function in the heart: Conduction abnormalities in Cantu syndrome.
abstract: BACKGROUND
  Gain-of-function (GOF) mutations in the KATP channel subunits Kir6.1 and SUR2 cause Cantu syndrome (CS), a disease characterized by multiple cardiovascular abnormalities.
  
  
  OBJECTIVE
  The purpose of this study was to better determine the electrophysiologic consequences of such GOF mutations in the heart.
  
  
  METHODS
  We generated transgenic mice (Kir6.1-GOF) expressing ATP-insensitive Kir6.1[G343D] subunits under α-myosin heavy chain (α-MHC) promoter control, to target gene expression specifically in cardiomyocytes, and performed patch-clamp experiments on isolated ventricular myocytes and invasive electrophysiology on anesthetized mice.
  
  
  RESULTS
  In Kir6.1-GOF ventricular myocytes, KATP channels showed decreased ATP sensitivity but no significant change in current density. Ambulatory ECG recordings on Kir6.1-GOF mice revealed AV nodal conduction abnormalities and junctional rhythm. Invasive electrophysiologic analyses revealed slowing of conduction and conduction failure through the AV node but no increase in susceptibility to atrial or ventricular ectopic activity. Surface ECGs recorded from CS patients also demonstrated first-degree AV block and fascicular block.
  
  
  CONCLUSIONS
  The primary electrophysiologic consequence of cardiac KATP GOF is on the conduction system, particularly the AV node, resulting in conduction abnormalities in CS patients who carry KATP GOF mutations.
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Levin
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Keita
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Gautam K
authors.initials: GK
authors.lastname: Singh
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri. Electronic address: cnichols@wustl.edu.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
mesh_terms: D000818:Animals; D054537:Atrioventricular Block / Q000235:genetics*; D053840:Brugada Syndrome / Q000235:genetics; D000075224:Cardiac Conduction System Disease; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics*; D002478:Cells, Cultured; D002675:Child, Preschool; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D004562:Electrocardiography; D055724:Electrophysiological Phenomena / Q000235:genetics; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D006983:Hypertrichosis / Q000000981:diagnostic imaging / Q000235:genetics*; D054086:KATP Channels / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics*; D011897:Random Allocation; D035583:Rare Diseases; D012494:Sampling Studies
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D054086:KATP Channels; C484274:KCNJ5 protein, human; C092520:uK-ATP-1 potassium channel
keywords: Cantu syndrome; Conduction system; K(ATP); KCNJ8; Kir6.1; Mouse in vivo electrophysiology; Transgenic