Program Project Focuses on Molecular Cause of Birth Defects in Genetic Syndrome


Multiple structural birth defects, slow growth, cardiac abnormalities and mental retardation are some of the hallmark characteristics of Cornelia de Lange syndrome (CdLS), a rare and little-known genetic disorder affecting 1 in 10,000 live births. An estimated 20,000 children in the U.S. have CdLS but most remain undiagnosed.

Although Children's Hospital investigators have shown that mutations in the Nipped-B-like (NIPBL) gene cause CdLS, the role of the gene's product remains largely unknown in humans and it is unclear how the mutations in this novel gene result in the multisystem problems seen in patients with CdLS.

A multicenter team led by Ian Krantz, M.D., Division of Human Genetics and Molecular Biology, hopes to unravel NIPBL's mysterious workings with the aid of a $5 million program project grant from the National Institute of Child Health and Human Development. The five-year award centers on gaining a better understanding of the molecular and developmental cause of many of the structural birth defects associated with CdLS.

Dr. Krantz leads the multisite team that includes other investigators from Children's Hospital, St. Louis University, the University of California at Irvine and Drexel University. Together, the researchers hope to characterize NIPBL's function, identify its target genes, and evaluate their roles in causing the birth defects often seen in CdLS.

The discovery that NIPBL causes CdLS provides a starting point to identify downstream genetic targets involved in the many structural and developmental defects that accompany this genetic disorder.

The investigators believe that the disruption of NIPBL's ability to facilitate long-range, enhancer-promoter interactions, and subsequent transcriptional dysregulation of key developmental genes, results in the birth defects seen in CdLS.

"We believe that NIPBL acts as a master switch for a number of important developmental genes that play individual roles in the specific systemic structural birth defects seen in CdLS, and the goal of this proposal is to identify what those targets are," says Dr. Krantz.

The three-pronged approach to studying NIPBL planned by Dr. Krantz and his colleagues focuses on the gene's pathways in humans and other models to synergistically characterize the function, interactions and role of NIPBL and its downstream targets.

"While the impact of disease gene identification on families with individuals affected by rare human disorders is tremendous, the true strength of these discoveries comes more from the insight they provide into the pathogenesis of more common and often isolated human structural developmental defects, the genes for which are much more difficult to map," says Dr. Krantz.