title: Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system.
abstract: Heterozygous mutations of the cardiac transcription factor Nkx2-5 cause atrioventricular conduction defects in humans by unknown mechanisms. We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage. Null mutant embryos appear to lack the primordium of the atrioventricular node. In Nkx2-5 haploinsufficiency, the conduction system has half the normal number of cells. In addition, an entire population of connexin40(-)/connexin45(+) cells is missing in the atrioventricular node of Nkx2-5 heterozygous KO mice. Specific functional defects associated with Nkx2-5 loss of function can be attributed to hypoplastic development of the relevant structures in the conduction system. Surprisingly, the cellular expression of connexin40, the major gap junction isoform of Purkinje fibers and a putative Nkx2-5 target, is unaffected, consistent with normal conduction times through the His-Purkinje system measured in vivo. Postnatal conduction defects in Nkx2-5 mutation may result at least in part from a defect in the genetic program that governs the recruitment or retention of embryonic cardiac myocytes in the conduction system.
authors.affiliation: Department of Cardiology, Children's Hospital, Boston, Massachusetts 02115, USA. patrick.jay@childrens.harvard.edu
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
authors.forename: Brett S
authors.initials: BS
authors.lastname: Harris
authors.forename: Colin T
authors.initials: CT
authors.lastname: Maguire
authors.forename: Antje
authors.initials: A
authors.lastname: Buerger
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Tanaka
authors.forename: Sabina
authors.initials: S
authors.lastname: Kupershmidt
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Schultheiss
authors.forename: Terrence X
authors.initials: TX
authors.lastname: O'Brien
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gourdie
authors.forename: Charles I
authors.initials: CI
authors.lastname: Berul
authors.forename: Seigo
authors.initials: S
authors.lastname: Izumo
mesh_terms: D000818:Animals; D017630:Connexins / Q000032:analysis; D004562:Electrocardiography; D006329:Heart Conduction System / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D018398:Homeodomain Proteins; D000097003:Gap Junction alpha-5 Protein