title: Cardiac conduction and arrhythmia: insights from Nkx2.5 mutations in mouse and humans.
abstract: The phenotypes of cardiac conduction and rhythm disorders are very well characterized because of the large numbers of affected patients who seek medical treatment. The few disorders where the genetic basis is known has led to a commonly held notion that the abnormal function of ion pumps, channels and connexins (ICC) causes conduction defects and arrhythmias. Although probably true in general, the ICC-centric model underemphasizes alternative mechanisms involving the organization of cells or mechanisms of gene expression. NKX2.5 was one of the first cardiac transcription factors identified that when mutated causes congenital heart disease and conduction defects in human. We present two hypotheses for the pathogenesis of conduction defects and arrhythmias as caused by transcription factor haploinsufficiency that are alternatives to a strictly ICC-centric model. First, conduction defects may arise from anatomic underdevelopment of the conduction system in utero. Second, the cardiac arrhythmias associated with Nkx2.5 mutation may result from the non-uniform alteration in a population of cardiac myocytes of the levels of channel proteins, leading to increased electrical heterogeneity. We propose that consideration of the two alternative hypotheses, in addition to the traditional ICC-centric model, should lead to a richer understanding of cardiac conduction defects and arrhythmogenesis.
authors.affiliation: Department of Cardiology, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
authors.forename: Charles I
authors.initials: CI
authors.lastname: Berul
authors.forename: Makoto
authors.initials: M
authors.lastname: Tanaka
authors.forename: Masao
authors.initials: M
authors.lastname: Ishii
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kurachi
authors.forename: Seigo
authors.initials: S
authors.lastname: Izumo
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D006329:Heart Conduction System / Q000502:physiology* / Q000503:physiopathology*; D006330:Heart Defects, Congenital / Q000473:pathology / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics
chemical_list: D017630:Connexins; D018398:Homeodomain Proteins; D014157:Transcription Factors