Edited by: Steven Benowitz
ALLELIC TWINS: Jackson-Weiss and Crouzon syndromes are both caused by FGFR2 mutation, notes Johns Hopkins researcher Ethylin Jabs.
Mutations in a group of proteins known as fibroblast growth factor receptors 2 (FGFR2) have been found in patients with Jackson-Weiss syndrome, in which the skull, face, and feet may be deformed, and another similar inherited disorder, Crouzon syndrome. One of the hallmarks of both diseases is craniosynostosis, in which the skull bones fuse prematurely, causing abnormally shaped skulls. The condition occurs in one in 3,000 newborns.
FGFRs are involved in many developmental processes, including cell maintenance, mitosis, embryogenesis, and angiogenesis. "A lot of processes will be affected by these mutations," says Ethylin Wang Jabs, a professor of pediatrics, medicine, and surgery at Johns Hopkins University School of Medicine. "FGFRs are ubiquitous, but there are four receptors with different isoforms, which have different roles. Some of these overlap, however."
In this paper, Jabs, who is director of the Johns Hopkins Center of Craniofacial Development and Disorders, and her coworkers describe how they found an FGFR2 mutation in both syndromes in the same region on chromosome 10.
Jabs and colleagues had previously mapped the mutated gene for Jackson-Weiss and Crouzon syndromes to the same chromosome 10 location (X. Li et al., Genomics, 22:418-24, 1994). Other researchers had established multiple FGFR2 mutations in Crouzon syndrome patients. The team wanted to find out if the same type of FGFR2 mutation was causing Jackson-Weiss.
To explore that theory, Jabs's group examined members of a family with Jackson-Weiss syndrome and members of 12 families with Crouzon syndrome. The team isolated DNA from 49 members of the Amish family in which Jackson-Weiss was first detected. They found the same FGFR2 mutation in all members and in the same region in which Crouzon syndrome mutations had been identified. In four of 12 Crouzon syndrome families, the researchers found two new and two previously described FGFR2 mutations. This shows that unrelated families can have the same genetic mutation.
Subsequent work has shown that the same gene mutations behind Crouzon and Jackson-Weiss syndromes can also cause another similar disorder, Pfieffer syndrome.
Jabs isn't sure why one disorder or another arises from the same gene mutation. "We need to find modifying genes that cause the variability among the diseases. In Jackson-Weiss syndrome, for example, the variability of symptoms is quite pronounced." She plans to search for these modifying genes and factors.
"We argue in the paper that because this [Jackson-Weiss syndrome] is all within one family-an Amish family with more than 100 people affected-we can see the disease variability [and study it]," she says.
After they found that Jackson-Weiss and Crouzon were caused by the same gene mutation, "it gave us clues to other related skin disorders, such as acanthosis nigricans [G.A. Meyers et al., Nature Genetics, 11:462-4, 1995] and Beare-Stevenson cutis gyrata syndrome [K.A. Przylepa et al., Nature Genetics, 13:492-4, 1996].
"It's very complicated," she concludes. "You can have the same mutation on the same gene and cause different conditions. You can have the same condition, and have mutations on different FGFRs-it works both ways."
Jabs suspects the paper has been frequently cited because it was "one of the first in the field and showed an example of another disorder caused by FGFR mutations. This was the beginning of finding more conditions caused by FGFR mutations."