"The moment we looked at the very first brain, it was so obvious they had a very messed up cerebellum and it had been completely overlooked," Millen said.

Now confident that FOXC1 was important for cerebellar development in mice, the researchers then searched for humans lacking all or part of the gene. Fortunately, they found 11 such subjects through Ordan Lehmann, associate professor of ophthalmology and medical genetics at the University of Alberta, who was studying patients with pediatric-onset glaucoma caused by FOXC1.

When the glaucoma patients were given MRI scans, the researchers observed cerebellar abnormalities that proved the involvement of FOXC1 in Dandy-Walker malformation.

"These patients were essential for blaming the brain malformation on the FOXC1 gene," Millen said. "Based on the mouse mutants we had a huge suspicion it had to be FOXC1, and the patients confirmed it."

The dramatic changes in the brains of these patients offers new insight into mechanisms contributing to glaucoma, a common disorder previously considered to be just a disease of the optic nerve - the nerve connecting the eye to the brain. Further studies of how the FOXC1 gene directs development of the cerebellum and other brain structures could also lead to new research avenues and treatments for hydrocephalous, autism and other diseases.

"Now that we understand what's going on, we can look at all the other loci and see if there are any other genes that fit this framework," Millen said. "From now on gene finding should be a lot faster because we understand the basic biology."

"This finding makes us rethink the basis of this disease," said Joseph Gleeson, M.D., an investigator with the Howard Hughes Medical Institute at the University of California, San Diego, who was not involved with the study. "It's going to be a shift from the way we were thinking about it to a new paradigm where there are a whole bunch of new ideas about how we understand Dandy-Walker malformation."