title: Function follows form: cardiac conduction system defects in Nkx2-5 mutation.
abstract: Mutations of Nkx2-5 cause congenital heart disease and atrioventricular block in man. The altered expression of an electrophysiologic protein regulated by Nkx2-5 was originally presumed to cause the conduction defect, but when no such protein was found, an alternative hypothesis was considered. In pediatric patients, the association of certain cardiac malformations with congenital atrioventricular block suggests that errors in specific developmental pathways could cause both an anatomic and a physiologic defect. We therefore hypothesized that Nkx2-5 insufficiency perturbs the conduction system during development, which in turn manifests as a postnatal conduction defect. Experimental results from Nkx2-5 knockout mouse models support the developmental hypothesis. Hypoplasia of the atrioventricular node, His bundle, and Purkinje system can explain in whole or in part specific conduction and electrophysiologic defects present in Nkx2-5 haploinsufficiency.
authors.affiliation: Department of Cardiology, Children's Hospital, Boston, Massachusetts, USA. jay_p@kids.wustl.edu
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
authors.forename: Brett S
authors.initials: BS
authors.lastname: Harris
authors.forename: Antje
authors.initials: A
authors.lastname: Buerger
authors.forename: Olga
authors.initials: O
authors.lastname: Rozhitskaya
authors.forename: Colin T
authors.initials: CT
authors.lastname: Maguire
authors.forename: Laura A
authors.initials: LA
authors.lastname: Barbosky
authors.forename: Ellen
authors.initials: E
authors.lastname: McCusty
authors.forename: Charles I
authors.initials: CI
authors.lastname: Berul
authors.forename: Terrence X
authors.initials: TX
authors.lastname: O'brien
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gourdie
authors.forename: Seigo
authors.initials: S
authors.lastname: Izumo
mesh_terms: D000818:Animals; D017630:Connexins / Q000378:metabolism*; D006329:Heart Conduction System / Q000196:embryology* / Q000473:pathology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097003:Gap Junction alpha-5 Protein; C484469:Nkx2-5 protein, mouse