Congenital heart defects are common human malformations that cause significant morbidity, mortality, in addition to substantial social and economic costs. Birth defect registries indicated congenital heart defects occur in approximately 1 percent of human lie births and 10 percent of stillbirths (1). Over the past 30 years major advances have occurred in the diagnosis and management of heart defects in infants and children. Far less is known about the normal molecular signals or pathways that direct human cardiac morphogenesis, nor how and why these processes sometimes fail. Application of human genetic analysis to the study of inherited congenital heart disease has enormous potential to provide novel insights into these complex human processes. The focus of this application is to define the molecular causes of inherited human congenital heart defects. The investigators have recently identified three loci that cause human cardiac malformations. (1) Holt-Oram syndrome which maps tot chromosome 12q2 is caused by mutations in human TBX5. This congenital malformation causes skeletal and ventricular septal defects and sinus or atrio- ventricular septal defects, and sinus or atrio-ventricular nodal abnormalities that arise independent of septation defects). (2) The investigators have recently mapped gene defects that cause non-syndromic secundum atrial septal defects with associated atrioventricular conduction delays to chromosome 5q and have demonstrated the causal gene at this locus to be Nkappax2.5 (also termed hCSx). (3) The investigators have defined a locus on chromosome 5p that causes non-syndromic secundum atrial septal defects without conduction defects. Individuals affected by mutations in the 5q and 5p loci may have normal cardiac structure, atrial septal aneurysm, bicuspid aortic valve, persistent left superior vena cava, or more complex structural defects (such as tetralogy of Fallot). This variable expressivity combined with reduced penetrance of these gene mutations have partially obscured the familial (and genetic) nature of these congenital heart defects. The investigators' data and studies by others clearly demonstrate genetic heterogeneity of human congenital heart disease. Further identification and characterization of mutations in known disease genes and those yet to be defined should therefore provide a better understanding of human cardiac morphogenesis and the molecular basis of cardiac malformations. Development and characterization of animal models with these mutations should help explain the variable expression of these mutations. Ultimately these studies may also improve the understanding of non-familial congenital heart disease. The investigators propose to address these issues through the following specific aims: (1) characterize further the clinical manifestations of human TBX5 and Nkappax2.5 mutations to elucidate structure/function relationships; (2) identify other gene defects that cause heritable cardiac malformations using positional cloning and candidate gene analyses; (3) engineer and characterize mice with human TBX5 mutations in other cardiac malformation genes; and (5) test the hypothesis that TBX5 is subject to allelic exclusion in some cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL061036-02
Application #
6302537
Study Section
Project Start
2000-01-25
Project End
2000-12-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
2
Fiscal Year
2000
Total Cost
$234,991
Indirect Cost
Name
Harvard University
Department
Type
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Pu, William T; Ishiwata, Takahiro; Juraszek, Amy L et al. (2004) GATA4 is a dosage-sensitive regulator of cardiac morphogenesis. Dev Biol 275:235-44
Kasahara, Hideko; Ueyama, Tomomi; Wakimoto, Hiroko et al. (2003) Nkx2.5 homeoprotein regulates expression of gap junction protein connexin 43 and sarcomere organization in postnatal cardiomyocytes. J Mol Cell Cardiol 35:243-56
Ueyama, Tomomi; Kasahara, Hideko; Ishiwata, Takahiro et al. (2003) Myocardin expression is regulated by Nkx2.5, and its function is required for cardiomyogenesis. Mol Cell Biol 23:9222-32
Ishiwata, Takahiro; Nakazawa, Makoto; Pu, William T et al. (2003) Developmental changes in ventricular diastolic function correlate with changes in ventricular myoarchitecture in normal mouse embryos. Circ Res 93:857-65
Ueyama, Tomomi; Kasahara, Hideko; Ishiwata, Takahiro et al. (2003) Csm, a cardiac-specific isoform of the RNA helicase Mov10l1, is regulated by Nkx2.5 in embryonic heart. J Biol Chem 278:28750-7
Rallis, Charalampos; Bruneau, Benoit G; Del Buono, Jo et al. (2003) Tbx5 is required for forelimb bud formation and continued outgrowth. Development 130:2741-51
Wakimoto, Hiroko; Kasahara, Hideko; Maguire, Colin T et al. (2002) Developmentally modulated cardiac conduction failure in transgenic mice with fetal or postnatal overexpression of DNA nonbinding mutant Nkx2.5. J Cardiovasc Electrophysiol 13:682-8
Triedman, John K; Alexander, Mark E; Love, Barry A et al. (2002) Influence of patient factors and ablative technologies on outcomes of radiofrequency ablation of intra-atrial re-entrant tachycardia in patients with congenital heart disease. J Am Coll Cardiol 39:1827-35
Kardon, Gabrielle; Campbell, Jacquie Kloetzli; Tabin, Clifford J (2002) Local extrinsic signals determine muscle and endothelial cell fate and patterning in the vertebrate limb. Dev Cell 3:533-45
Gehrmann, J; Frantz, S; Maguire, C T et al. (2001) Electrophysiological characterization of murine myocardial ischemia and infarction. Basic Res Cardiol 96:237-50

Showing the most recent 10 out of 16 publications