Human Studies and Mouse Models Provide Insight into Diaphragm Development

Abstract

Congenital diaphragmatic hernia (CDH) is a common life-threatening birth defect, with an incidence of approximately 1:4,000 live births. To understand the molecular mechanisms and developmental processes that cause CDH, we must first identify the genes that are required for normal diaphragm development. The sporadic nature of CDH makes a linkage-based approach to gene identification impractical. However, advances in molecular cytogenetic techniques have provided an alternative approach in which CDH-related genes are being mapped and identified using a positional candidate strategy. To date, over 20 chromosomal regions that are recurrently deleted or duplicated in patients with CDH have been identified. Although sequencing efforts have revealed relatively few mutations within positional candidate genes, mouse models suggest that alterations in several genes within these regions contribute to the development of CDH in humans. Many of the genes that cause CDH in mice—including Gata4, Fog2, and Nr2f2—play a role in retinoic acid signaling while others—including Frem1 and Slit3—encode extracellular matrix proteins. Careful phenotypic and molecular analyses of these mouse models have provided, and will continue to provide, important insights into diaphragm development and the causes of CDH in humans.