Elsevier

Cardiovascular Pathology

Volume 17, Issue 1, January–February 2008, Pages 48-54
Cardiovascular Pathology

Review Article
Genetic insights into normal and abnormal heart development,☆☆

https://doi.org/10.1016/j.carpath.2007.06.005Get rights and content

Abstract

Congenital heart defects (CHDs) affect 1–2% of newborn children and are the leading cause of death in infants under 1 year of age. CHDs represent the single largest class of birth defects and account for 25% of all human congenital abnormalities. Numerous epidemiologic studies have established the heritable nature of CHDs. However, despite the remarkable progress of the past decade, very few CHD-causing genes have been identified so far. Molecular and genetic analysis of heart development—which requires the execution of specific genetic programs—has led to the identification of essential cardiac regulators and mutations that are linked to human CHD. Elucidation of the mechanisms of action of these transcription factors has also provided a molecular framework that will continue to help furthering our understanding of the molecular basis of normal and abnormal heart growth. This review will summarize present knowledge of cardiac development and illustrate how analysis of heart development has helped understand the genetic basis of some CHDs and how these advances could translate into better prevention, diagnosis, and care of congenital heart disease.

Section snippets

Heart development: from lineages to chambers

In higher vertebrates, heart formation is a complex process (Fig. 1) that starts at early stages of embryogenesis, prior to the end of gastrulation, with commitment of anterior lateral plate mesoderm cells to the cardiogenic lineage and their migration and organization into the cardiac crescent. Commitment to a cardiac fate is the result of inductive signals from the underlying endoderm, which include bone morphogenetic proteins (BMPs), basic fibroblast growth factors, and the Wnt proteins. The

Cardiac transcription: a multipartner affair

The complex morphologic events and tissue remodeling that take place during heart formation are accompanied by equally complex changes of gene expression that produce dynamically regulated chamber as well as left–right specific patterns. Despite important efforts devoted to the study of chamber-specific gene expression and the identification of several cardiac TFs involved in heart formation (Fig. 1 and Table 1), the molecular mechanisms underlying spatiotemporal regulation of transcription

CHD: an enigma of variable expressivity and multiple genes

Septal and valvular defects are the most frequently occurring CHDs [45]. They range in severity from relatively minor, even subclinical defects like patent foramen oval (PFO), to complex malformations like tetralogy of Fallot or tricuspid atresia that can be life threatening. Although minor subclinical defects do not interfere significantly with heart function initially, with time, they can impair exercise tolerance, such as atrial septal defects (ASDs), and in general, they represent risk

Conclusion and future directions

Cardiac development is a complex and highly regulated interplay of genes and cell–cell interactions. The past decade has witnessed spectacular progress in elucidating the molecular mechanisms of heart formation. In particular, several genes essential for heart development have been identified. Genetic analysis using classical human genetic approaches, as well as the direct sequencing of candidate genes—which are essential for normal heart formation—in families with affected members, has started

Acknowledgment

I am indebted to past and present members of my laboratory for their invaluable contributions over the years. Special thanks to L. Laroche for excellent secretarial support and P. Paradis for editorial assistance. M.N. holds the Canada Research Chair in Cardiovascular Growth and Differentiation.

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    The work carried out in the author's laboratory is supported by the Canadian Institutes of Health Research.

    ☆☆

    This article is based on a presentation at the Society for Cardiovascular Pathology Companion Meeting at the United States and Canadian Academy of Pathology, San Diego, CA, February 2007.

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