Mouse Model of Human Congenital Heart Disease

Progressive Atrioventricular Block Induced by a Heterozygous Nkx2-5 Homeodomain Missense Mutation

Rajib Chowdhury, Hassan Ashraf, Michelle Melanson, Yohei Tanada, Minh Nguyen, Gary (Michael) Silberbach, Hiroko Wakimoto, D. Woodrow Benson, Robert H. Anderson, Hideko Kasahara

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1255-1264
Number of pages10
JournalCirculation: Arrhythmia and Electrophysiology
Volume8
Issue number5
DOIs
StatePublished - Oct 1 2015

Fingerprint

Atrioventricular Block
Missense Mutation
Heart Diseases
Electrophysiology
Right Ventricular Function
Atrioventricular Node
Telemetry
Congenital Heart Defects
Electrocardiography
Phenotype
DNA

Keywords

  • animal models
  • atrioventricular block
  • congenital heart defects
  • genetics
  • human

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Mouse Model of Human Congenital Heart Disease : Progressive Atrioventricular Block Induced by a Heterozygous Nkx2-5 Homeodomain Missense Mutation. / Chowdhury, Rajib; Ashraf, Hassan; Melanson, Michelle; Tanada, Yohei; Nguyen, Minh; Silberbach, Gary (Michael); Wakimoto, Hiroko; Benson, D. Woodrow; Anderson, Robert H.; Kasahara, Hideko.

In: Circulation: Arrhythmia and Electrophysiology, Vol. 8, No. 5, 01.10.2015, p. 1255-1264.

Research output: Contribution to journalArticle

Chowdhury, Rajib ; Ashraf, Hassan ; Melanson, Michelle ; Tanada, Yohei ; Nguyen, Minh ; Silberbach, Gary (Michael) ; Wakimoto, Hiroko ; Benson, D. Woodrow ; Anderson, Robert H. ; Kasahara, Hideko. / Mouse Model of Human Congenital Heart Disease : Progressive Atrioventricular Block Induced by a Heterozygous Nkx2-5 Homeodomain Missense Mutation. In: Circulation: Arrhythmia and Electrophysiology. 2015 ; Vol. 8, No. 5. pp. 1255-1264.
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abstract = "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.",
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T2 - Progressive Atrioventricular Block Induced by a Heterozygous Nkx2-5 Homeodomain Missense Mutation

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AU - Ashraf, Hassan

AU - Melanson, Michelle

AU - Tanada, Yohei

AU - Nguyen, Minh

AU - Silberbach, Gary (Michael)

AU - Wakimoto, Hiroko

AU - Benson, D. Woodrow

AU - Anderson, Robert H.

AU - Kasahara, Hideko

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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.

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