Progressive atrioventricular conduction defects and heart failure in mice expressing a mutant Csx/Nkx2.5 homeoprotein.
A DNA nonbinding mutant of the NK2 class homeoprotein Nkx2.5 dominantly inhibits cardiogenesis in Xenopus embryos, causing a small heart to develop or blocking heart formation entirely. Recently, ten heterozygous CSX/NKX2.5 homeoprotein mutations were identified in patients with congenital atrioventricular (AV) conduction defects. All four missense mutations identified in the human homeodomain led to markedly reduced DNA binding. To examine the effect of a DNA binding-impaired mutant of mouse Csx/Nkx2.5 in the embryonic heart, we generated transgenic mice expressing one such allele, I183P, under the beta-myosin heavy chain promoter. Unexpectedly, transgenic mice were born apparently normal, but the accumulation of Csx/Nkx2.5(I183P) mutant protein in the embryo, neonate, and adult myocardium resulted in progressive and profound cardiac conduction defects and heart failure. P-R prolongation observed at 2 weeks of age rapidly progressed into complete AV block as early as 4 weeks of age. Expression of connexins 40 and 43 was dramatically decreased in the transgenic heart, which may contribute to the conduction defects in the transgenic mice. This transgenic mouse model may be useful in the study of the pathogenesis of cardiac dysfunction associated with CSX/NKX2.5 mutations in humans.
Kasahara
H
H
Cardiovascular Division, Beth Israel Deaconess Medical Center, and Department of Medicine, Children's Hospital, Boston, Massachusetts, USA. hkasahar@caregroup.harvard.edu
Wakimoto
H
H
Liu
M
M
Maguire
C T
CT
Converso
K L
KL
Shioi
T
T
Huang
W Y
WY
Manning
W J
WJ
Paul
D
D
Lawitts
J
J
Berul
C I
CI
Izumo
S
S
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001283:Atrioventricular Node / Q000002:abnormalities / Q000503:physiopathology*; D001835:Body Weight; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000196:embryology / Q000254:growth & development; D006330:Heart Defects, Congenital / Q000150:complications / Q000503:physiopathology*; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009929:Organ Size; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins; D000097003:Gap Junction alpha-5 Protein
D018031:Connexin 43; D017630:Connexins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D014157:Transcription Factors; D029867:Xenopus Proteins; D000097003:Gap Junction alpha-5 Protein; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse