An international team of scientists studying a rare genetic disease discovered that a bundle of proteins with the long-established function of keeping chromosomes together also plays an important role in regulating genes in humans.

When gene regulation is disrupted in the multisystem genetic disease Cornelia deLange syndrome (CdLS), children may suffer missing hands or fingers, mental retardation, growth failure, cleft palate, heart defects, and other impairments. For families and patients, better knowledge of how those genes perturb normal development may enable researchers to design better diagnostic tests for the disease, and also provide targets for eventual treatments.

The study appeared today in the online journal Public Library of Science Biology (PloS Biology). The study leader was Ian D. Krantz, M.D., a specialist in pediatric genetics at The Children's Hospital of Philadelphia, where he directs a unique full-service clinic for children with CdLS.

First described in 1933, CdLS affects multiple organs and typically results in distinctive facial features, such as thin eyebrows that join, long eyelashes, thin lips, and excessive body hair. It affects an estimated one in 10,000 children. In the past, CdLS was only recognized in its very severe form that was often fatal in childhood; now most children with the condition live into adulthood. CdLS has a wide range of severity, with the mildest form manifesting as apparent isolated mental retardation and/or autism.

Krantz and colleagues investigated cohesin, a protein complex consisting of at least four proteins that form a ring that encircles chromosomes during cell division. Cohesin's long-established role, called "canonical" by the authors, is to control chromatids—the long strands that chromosomes form when they copy their DNA.

However, said Krantz, one open question is biology has been, "What does cohesin do when cells are not dividing?" His team's paper provides part of the answer, as the first study in human cells to identify genes that are dysregulated when cohesin doesn't work properly. Cohesin's role in dysregulation of gene expression (regulating the degree to which specific genes are turned on or off) has attracted considerable scientific interest with a recent discovery that it may also be implicated in cancer.

The current study builds on previous work by Krantz, who in 2004 co-led the study that discovered NIPBL, the first gene known to cause CdLS. Krantz partnered with his long-time collaborator, Laird S. Jackson, M.D., of Drexel University School of Medicine in Philadelphia. They discovered a second CdLS gene in 2007, and together they maintain the world's largest database of patients with CdLS.

In the current study, Krantz did a genome-wide analysis of mutant cell lines from 16 patients with severe CdLS. All the cells had mutations in the NIPBL gene, which plays a role in moving cohesin onto and off chromosomes.

The researchers used DNA microarrays, manufactured chips that measure how strongly different genes are expressed throughout a cell's full complement of DNA. The study team identified hundreds of genes that were dysregulated compared to controls, and also detected gene expression profiles that were unique to CdLS. Importantly, said Krantz, the expression levels of genes corresponded to the severity of the disease. The team replicated its findings in 101 additional samples.

"We found that gene expression is exquisitely regulated by cohesin and the NIBPL gene," said Krantz. "The gene expression patterns we found have great potential to be used in a diagnostic tool for Cornelia de Lange syndrome." He added that a gene array might also be developed as a single-platform tool to diagnose, from a patient's blood sample, not only CdLS, but also a variety of other developmental disorders.

Funding for the study came from the National Institute of Child Health and Development of the National Institutes of Health, the Pennsylvania Department of Health, the Genome Network Project and Grant-in-Aid for Scientific Research from the MEXT, a Japanese government ministry. First author Jinglan Liu receives a Cornelia de Lange Foundation Fellowship Grant.

Krantz's co-authors on the study came from Children's Hospital; the University of Pennsylvania School of Medicine; Drexel University School of Medicine; the Tokyo Institute of Technology; the Misakaenosono Mutsumi Developmental, Medical, and Welfare Center, in Isahaya, Japan; and the National University of Colombia, in Bogota, Colombia.

Liu et al, "Transcriptional dysregulation in NIPBL and cohesin mutant human cells," PloS Biology, published online, May 26, 2009.

About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit www.chop.edu.

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