title: Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death.
abstract: BACKGROUND
  Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in patients with diabetes mellitus. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia-susceptibility genes, including the KCNE2 K(+) channel β subunit, are expressed in multiple tissues, suggesting potential multiplex SCD substrates.
  
  
  RESULTS
  Using whole-transcript transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2(-/-) mouse pups and adrenal remodeling consistent with metabolic syndrome in adult Kcne2(-/-) mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes mellitus, hypercholesterolemia, hyperkalemia, anemia, and elevated angiotensin II. Kcne2 deletion was also a prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately after transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia, and AV block.
  
  
  CONCLUSIONS
  Disruption of a single, widely expressed arrhythmia-susceptibility gene can generate a multisystem syndrome comprising manifold electric and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia-susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins.
authors.affiliation: Bioelectricity Laboratory, Departments of Pharmacology and Physiology and Biophysics, School of Medicine, University of California, Irvine.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Hu
authors.forename: Ritu
authors.initials: R
authors.lastname: Kant
authors.forename: Marie
authors.initials: M
authors.lastname: Anand
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: King
authors.forename: Trine
authors.initials: T
authors.lastname: Krogh-Madsen
authors.forename: David J
authors.initials: DJ
authors.lastname: Christini
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Abbott
mesh_terms: D000740:Anemia / Q000209:etiology; D000804:Angiotensin II / Q000378:metabolism; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000473:pathology; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D003920:Diabetes Mellitus / Q000209:etiology; D050171:Dyslipidemias / Q000209:etiology; D053263:Gene Regulatory Networks; D005838:Genotype; D006579:Heterozygote; D006947:Hyperkalemia / Q000209:etiology; D007511:Ischemia / Q000209:etiology; D008133:Long QT Syndrome / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D024642:Potassium Channels, Voltage-Gated / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: C489620:Kcne2 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D000808:Angiotensinogen; D000804:Angiotensin II
keywords: arrhythmias, cardiac; death; ion channels; ischemia; potassium; sudden, cardiac