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[Congenital heart disease, heterotaxia and laterality]
José Manuel Icardo1, Juan Manuel García Rincón, María Angeles Ros
1Departamento de Anatomía y Biología Celular, Facultad de Medicina, Universidad de Cantabria, Santander, Spain. lcardojm@unican.es
Insights
Congenital heart disease can stem from single gene defects impacting embryonic development and laterality. Anomalous gene expression, like Nodal and Pitx2, can lead to heterotaxia syndrome and heart malformations.
Area of Science:
- Developmental Biology
- Genetics
- Embryology
Context:
- Congenital heart disease (CHD) affects approximately 0.8% of newborns.
- While often multifactorial, some CHDs result from single gene defects.
- Genetic defects can cause polymorphic presentations due to disruption of fundamental embryonic processes.
Purpose:
- To explore the role of single gene defects in congenital heart disease.
- To investigate the link between laterality establishment genes and heart malformations.
- To illustrate these concepts using the mouse mutant iv/iv model.
Summary:
- Single gene defects can lead to complex, polymorphic congenital heart disease by disrupting embryonic processes like left-right asymmetry.
- Genes controlling laterality, such as Nodal and Pitx2, are crucial; their anomalous expression can cause heterotaxia syndrome and associated heart defects.
- The mouse mutant iv/iv serves as a model for understanding heterotaxia syndrome and its cardiac manifestations.
Impact:
- Highlights the critical role of specific genes in normal heart development and laterality.
- Provides insights into the genetic basis of heterotaxia syndrome and congenital heart disease.
- Informs potential future research into genetic therapies or diagnostics for certain CHDs.
Abstract:
Congenital heart disease occurs in about 0,8% of all newborns. Many cardiac malformations occur among relatives and have a polymorphic presentation. The origin of most congenital heart disease is thought to be multifactorial, implying both anomalous expression of genes and the influence of epigenetic factors. However, in a small number of cases, the origin of congenital heart disease has been directly related to chromosomal anomalies or to defects in a single gene. Curiously, defects in a single gene can explain a polymorphic presentation if the anomalous gene controls a basic embryonic process that affects different organs in time and space. Some of these genes appear to control the establishment of laterality. The establishment of the left-right asymmetry starts at the Hensen node. Here, the initial embryonic symmetry is broken by cascades of gene activation that confer specific properties on the left and right sides of the embryo. Although there are variations between species, some basic patterns of gene expression (Nodal, Pitx2) appear to be maintained along the phylogenetic scale. Anomalous expression of these genes induces the heterotaxia syndrome, which usually courses with congenital heart disease. The development of heart malformations is illustrated with the mouse mutant iv/iv, which is a model for the heterotaxia syndrome and the associated congenital heart disease.