EMBARGOED FOR RELEASE: 5:00 p.m., EDT, June 26, 1997
Contact: Sarah Jarvis, (215) 590-4092, e-mail address: Jarvis @email.chop.edu
SCIENTISTS AT THE CHILDREN'S HOSPITAL OF PHILADELPHIA IDENTIFY GENETIC BASIS OF ALAGILLE SYNDROME
Discovery will permit identification of individuals who carry mutation
PHILADELPHIA--A report in the July 1997 issue of Nature Genetics offers new hope for families affected with the genetic disorder Alagille syndrome. Nancy Spinner, Ph.D., and a team of geneticists at The Children's Hospital of Philadelphia have demonstrated that mutations in a gene dubbed "Jagged 1" are responsible for the developmental disorder, which affects structures in the liver, heart, skeleton, eye, face, kidney and other organs.
Alagille syndrome occurs relatively infrequently, in about one of every 70,000 live births, and is a relatively common cause of liver and bile duct abnormalities in children. It is transmitted in an autosomal dominant fashion, which means that only one parent need carry the gene for a child to be affected. The degree to which an individual is affected varies widely, ranging from slight differences in facial appearance and mild heart murmur to serious liver and heart disease. As many as 15 percent of patients will require liver transplantation and 7-10 percent are born with severe congenital heart disease. Prior to the discovery of the genetic mutation responsible for the disorder, it has been difficult to diagnose the disease and even harder to determine who carries the mutation and is thus at risk of passing it on to future generations.
Spinner became interested in the genetics of Alagille syndrome because so many of these patients are seen at The Children's Hospital of Philadelphia by pediatric gastroenterologist David A. Piccoli, M.D. Earlier research in Spinner's lab mapped the genetic defect to a segment of chromosome 20. The next step was to find the specific location of the gene.
Across the country, scientists working at the University of Washington, in the laboratory of molecular biologist Leroy Hood, cloned the gene human Jagged 1 (hJagged1) and showed that it was located in the region of chromosome 20 near the site of the Alagille syndrome gene. Hood proposed hJagged1 as a candidate gene for Alagille syndrome. Spinner's lab had tested other known genes as possible candidates for the disorder, but this gene seemed particularly promising. The Jagged1 gene is related to a gene originally identified in the fruit fly, Drosophila, which had been shown to be involved in cell fate decisions- -what makes a cell choose a certain pathway during development. Problems in determining cell fate could explain some of the most prominent features of Alagille syndrome, such as the paucity of bile ducts in the liver.
After mapping hJagged1 to the Alagille syndrome critical region, Spinner began studying the mutations in four families affected with Alagille syndrome. In each case, mutations in the hJagged1 gene were found, indicating that Jagged is the causal gene for Alagille syndrome.
"One of the reasons this is exciting for the families is that, until now, people have not been able to tell who is a carrier," said Spinner . A parent who carries the gene may not exhibit apparent signs: only after the birth of a more severely affected child does the genetic defect come to light. For couples who want to have another child after having one affected child, knowing which parent carries the gene is crucial.
The discovery is also interesting from a basic scientific perspective, adds Spinner. "This gene has extensive similarity to genes found in flies, worms and rats; and work in these organisms has demonstrated that these genes play a key role in the development of multiple organ systems. The fact that this gene, which was first found in wing development in the fly, turns out to be the cause of a human genetic disease is exciting," said Spinner. This should also lead to further investigations of how the mutation produces disease and why the expression of the disease is so variable. Spinner has proposed that the syndrome results from an insufficiency of the hJagged1 protein. "We're just at the beginning of understanding this," she said.
The Children's Hospital of Philadelphia, the nation's first children's hospital, is a leader in patient care, education and research. This 304-bed multispecialty hospital provides comprehensive pediatric services to children from birth through age 19. This release is embargoed until 5 p.m. (EDT) on Thursday, June 26, 1997. To interview Dr. Spinner or one of the families who participated in this study, please contact Sarah Jarvis at 215-590-4092.
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