Function follows form: cardiac conduction system defects in Nkx2-5 mutation.
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.
Jay
Patrick Y
PY
Department of Cardiology, Children's Hospital, Boston, Massachusetts, USA. jay_p@kids.wustl.edu
Harris
Brett S
BS
Buerger
Antje
A
Rozhitskaya
Olga
O
Maguire
Colin T
CT
Barbosky
Laura A
LA
McCusty
Ellen
E
Berul
Charles I
CI
O'brien
Terrence X
TX
Gourdie
Robert G
RG
Izumo
Seigo
S
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
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