TY - JOUR
T1 - Mouse Model of Human Congenital Heart Disease
T2 - Progressive Atrioventricular Block Induced by a Heterozygous Nkx2-5 Homeodomain Missense Mutation
AU - Chowdhury, Rajib
AU - Ashraf, Hassan
AU - Melanson, Michelle
AU - Tanada, Yohei
AU - Nguyen, Minh
AU - Silberbach, Michael
AU - Wakimoto, Hiroko
AU - Benson, D. Woodrow
AU - Anderson, Robert H.
AU - Kasahara, Hideko
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Background - Heterozygous human NKX2-5 homeodomain (DNA-binding domain) missense mutations are highly penetrant for varied congenital heart defects, including progressive atrioventricular (AV) block requiring pacemaker implantation. We recently replicated this genetic defect in a murine knockin model, in which we demonstrated highly penetrant, pleiotropic cardiac anomalies. In this study, we examined postnatal AV conduction in the knockin mice. Methods and Results - A murine knockin model (Arg52Gly, Nkx2-5 +/R52G) in a 129/Sv background was analyzed by histopathology, surface, and telemetry ECG, and in vivo electrophysiology studies, comparing with control Nkx2-5 +/+ mice at diverse postnatal stages, ranging from postnatal day 1 (P1) to 17 months. PR prolongation (first degree AV block) was present at 4 weeks, 7 months, and 17 months of age, but not at P1 in the mutant mice. Advanced AV block was also occasionally demonstrated in the mutant mice. Electrophysiology studies showed that AV nodal function and right ventricular effective refractory period were impaired in the mutant mice, whereas sinus nodal function was not affected. AV nodal size was significantly smaller in the mutant mice than their controls at 4 weeks of age, corresponding to the presence of PR prolongation, but not P1, suggesting, at least in part, that the conduction abnormalities are the result of a morphologically atrophic AV node. Conclusions - The highly penetrant and progressive AV block phenotype seen in human heterozygous missense mutations in NKX2-5 homeodomain was replicated in mice by knocking in a comparable missense mutation.
AB - Background - Heterozygous human NKX2-5 homeodomain (DNA-binding domain) missense mutations are highly penetrant for varied congenital heart defects, including progressive atrioventricular (AV) block requiring pacemaker implantation. We recently replicated this genetic defect in a murine knockin model, in which we demonstrated highly penetrant, pleiotropic cardiac anomalies. In this study, we examined postnatal AV conduction in the knockin mice. Methods and Results - A murine knockin model (Arg52Gly, Nkx2-5 +/R52G) in a 129/Sv background was analyzed by histopathology, surface, and telemetry ECG, and in vivo electrophysiology studies, comparing with control Nkx2-5 +/+ mice at diverse postnatal stages, ranging from postnatal day 1 (P1) to 17 months. PR prolongation (first degree AV block) was present at 4 weeks, 7 months, and 17 months of age, but not at P1 in the mutant mice. Advanced AV block was also occasionally demonstrated in the mutant mice. Electrophysiology studies showed that AV nodal function and right ventricular effective refractory period were impaired in the mutant mice, whereas sinus nodal function was not affected. AV nodal size was significantly smaller in the mutant mice than their controls at 4 weeks of age, corresponding to the presence of PR prolongation, but not P1, suggesting, at least in part, that the conduction abnormalities are the result of a morphologically atrophic AV node. Conclusions - The highly penetrant and progressive AV block phenotype seen in human heterozygous missense mutations in NKX2-5 homeodomain was replicated in mice by knocking in a comparable missense mutation.
KW - animal models
KW - atrioventricular block
KW - congenital heart defects
KW - genetics
KW - human
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U2 - 10.1161/CIRCEP.115.002720
DO - 10.1161/CIRCEP.115.002720
M3 - Article
C2 - 26226998
AN - SCOPUS:84944676794
SN - 1941-3149
VL - 8
SP - 1255
EP - 1264
JO - Circulation: Arrhythmia and Electrophysiology
JF - Circulation: Arrhythmia and Electrophysiology
IS - 5
ER -