Research May Lead to Screening and Rapid Diagnosis of Disease That Can Cause Disfigurement, Mental Retardation and Death
An international team of researchers, including biologists from UC Irvine, has discovered the gene for Cornelia de Lange syndrome, a disabling, multisystem genetic disease that affects about one in 10,000 children. The finding is expected to lead to a genetic test, enabling rapid and definitive diagnosis of the syndrome, as well as prenatal testing for families who already have one child with the disease. UCI biologists Arthur Lander and Anne Calof participated in the study, which was led by geneticists from The Children’s Hospital of Philadelphia and Drexel University College of Medicine in Philadelphia. The study received advance publication on May 16 on the Web site of Nature Genetics. Named for a Dutch physician who first described it in 1933, Cornelia de Lange syndrome often includes mental retardation, impaired growth, heart defects, gastroesophageal reflux and feeding problems, impaired vision, hearing loss and upper limb abnormalities, including missing fingers or hands. There are typically distinctive facial features, such as thin eyebrows that join together, long eyelashes, thin lips and excessive body hair. In the past, CdLS was often fatal in infancy; now, most children with the condition live into adulthood. Although CdLS has been known for decades, the disease is a challenge to scientists. The syndrome is also variable — some patients have much milder manifestations. In addition, because few individuals with CdLS have children, it is rare to find parents and children who both have the disease. “Because CdLS doesn't usually run in families, this was a difficult gene to find,� Lander said. “Knowing the gene's identity will allow for better and faster diagnosis, as well as new therapeutic approaches aimed at treating the underlying causes of the disorder." The lead researchers, Dr. Ian D. Krantz of Children’s Hospital and Dr. Laird G. Jackson of Drexel University College of Medicine, together maintain the world’s largest database of patients with Cornelia de Lange syndrome, drawing on clinical records and genetic samples first gathered 30 years ago. Lander, Calof and UCI postdoctoral researcher Shimako Kawauchi were responsible for determining where the CdLS gene is expressed in embryonic mice. Since early development is very similar between mouse and man, this information suggests the likely sites of gene action in human embryos. In the current study, the researchers analyzed the genomes of 12 families having more than one member with CdLS. Through a process of elimination, they were able to identify four possible regions for the CdLS gene. Further analysis narrowed the search to a region of chromosome 5. They combined this knowledge with cytogenetic data — the details of chromosomal rearrangements in a child with CdLS. The team identified a large gene on chromosome 5, which they named NIPBL. Mutations giving rise to Cornelia de Lange syndrome occur at different locations within that gene. NIPBL stands for Nipped B-like, because the human gene produces proteins similar to those produced by the Nipped-B gene in fruit flies. Both the fruit fly gene and the human gene regulate biological signals that have wide-ranging effects on a variety of organ systems during development. Lander is the chair and professor of developmental and cell biology, and Calof is an associate professor of anatomy and neurobiology with a joint appointment in developmental and cell biology. The study’s authors represent five hospitals and eight universities from four countries. In addition, co-authors participated from the University of Pennsylvania School of Medicine, Philadelphia; Nemours Children's Clinic, Wilmington, Del.; Geneva University Hospital, Switzerland; the University of Genoa, Italy; the University of Nevada School of Medicine; University Medical Centre, Hamilton, Ontario, Canada; Michigan State University; and the University of Utah Health Sciences Center. About the University of California, Irvine: The University of California, Irvine is a top-ranked public university dedicated to research, scholarship and community. Founded in 1965, UCI is among the fastest-growing University of California campuses, with approximately 24,000 undergraduate and graduate students and about 1,300 faculty members. The third-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3 billion. ---------- A complete archive of press releases is available on the World Wide Web at www.communications.uci.edu