title: A novel genetic pathway for sudden cardiac death via defects in the transition between ventricular and conduction system cell lineages.
abstract: HF-1 b, an SP1 -related transcription factor, is preferentially expressed in the cardiac conduction system and ventricular myocytes in the heart. Mice deficient for HF-1 b survive to term and exhibit normal cardiac structure and function but display sudden cardiac death and a complete penetrance of conduction system defects, including spontaneous ventricular tachycardia and a high incidence of AV block. Continuous electrocardiographic recordings clearly documented cardiac arrhythmogenesis as the cause of death. Single-cell analysis revealed an anatomic substrate for arrhythmogenesis, including a decrease and mislocalization of connexins and a marked increase in action potential heterogeneity. Two independent markers reveal defects in the formation of ventricular Purkinje fibers. These studies identify a novel genetic pathway for sudden cardiac death via defects in the transition between ventricular and conduction system cell lineages.
authors.affiliation: UCSD-Salk Program in Molecular Medicine and the UCSD Institute of Molecular Medicine, University of California, San Diego, La Jolla 92093, USA.
authors.forename: V T
authors.initials: VT
authors.lastname: Nguyên-Trân
authors.forename: S W
authors.initials: SW
authors.lastname: Kubalak
authors.forename: S
authors.initials: S
authors.lastname: Minamisawa
authors.forename: C
authors.initials: C
authors.lastname: Fiset
authors.forename: K C
authors.initials: KC
authors.lastname: Wollert
authors.forename: A B
authors.initials: AB
authors.lastname: Brown
authors.forename: P
authors.initials: P
authors.lastname: Ruiz-Lozano
authors.forename: S
authors.initials: S
authors.lastname: Barrere-Lemaire
authors.forename: R
authors.initials: R
authors.lastname: Kondo
authors.forename: L W
authors.initials: LW
authors.lastname: Norman
authors.forename: R G
authors.initials: RG
authors.lastname: Gourdie
authors.forename: M M
authors.initials: MM
authors.lastname: Rahme
authors.forename: G K
authors.initials: GK
authors.lastname: Feld
authors.forename: R B
authors.initials: RB
authors.lastname: Clark
authors.forename: W R
authors.initials: WR
authors.lastname: Giles
authors.forename: K R
authors.initials: KR
authors.lastname: Chien
mesh_terms: D000200:Action Potentials; D000483:Alleles; D000818:Animals; D002452:Cell Count; D019070:Cell Lineage; D017630:Connexins / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016757:Death, Sudden, Cardiac / Q000473:pathology*; D004553:Electric Conductivity; D004562:Electrocardiography; D005260:Female; D017353:Gene Deletion; D006327:Heart Block / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006329:Heart Conduction System / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D006352:Heart Ventricles / Q000196:embryology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019683:Penetrance; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000032:analysis / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011690:Purkinje Fibers / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011845:Radio; D051706:Sp4 Transcription Factor; D017180:Tachycardia, Ventricular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013686:Telemetry; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D004268:DNA-Binding Proteins; D011188:Potassium; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D051706:Sp4 Transcription Factor; D000097003:Gap Junction alpha-5 Protein; C081928:Sp4 protein, rat; C059983:potassium channel protein I(sk)