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August 23, 2004
August 23, 2004
Thanks to a productive collaboration between clinical and basic scientists, researchers from the University of Chicago have identified the first genetic cause of one of the most common birth defects of the brain, Dandy-Walker malformation (DWM). Infants with this disorder, about one in 10,000 births, have a small, displaced cerebellum and other brain abnormalities that can reduce coordination, impair mental function and cause hydrocephalus.
In the September 2004, issue of Nature Genetics--to be published online August 22--the researchers show that in humans, loss of one copy of each of two adjacent genes, known as ZIC1 and ZIC4, causes Dandy-Walker. The researchers then used this finding to create a mouse model to allow them to study the developmental basis of the disorder.
"Dandy-Walker malformation is an important clinical problem as well as a scientific mystery," said study co-author William Dobyns, MD, professor of human genetics, neurology and pediatrics at the University of Chicago and an author of the study. "We see about 20 cases per year, but until recently, there was not even an understanding that Dandy-Walker had a genetic basis."
"Knowing more about the genes also should improve our ability to make a prenatal diagnosis," he added, "which has always relied upon ultrasound. Finding the genes will help us inform parents about the risks of having another affected child."
"This discovery provides one of the first real avenues for understanding human birth defects that affect the cerebellum," said study author Kathleen Millen, PhD, assistant professor of human genetics at the University of Chicago. "Until now, we have had no understanding of what goes wrong during development to cause this malformation. We now know some of the genes involved and have a mouse model to study to figure this out."
This work may also have broader implications. Understanding what goes wrong in Dandy-Walker malformation could provide clues about autism, in which similar but much milder cerebellar abnormalities are common.
The hunt for the Dandy-Walker genes began when a child from Kansas with a missing piece of chromosome 3 was found to have DWM and was referred to Dr. Dobyns for an evaluation. Inspired by this clue, Inessa Grinberg, an MD/PhD student working with Millen and Dobyns, began to scour the Internet looking for parent support web sites for children with DWM, and for separate web sites for parents of children with chromosome 3 abnormalities.
The team eventually found eight patients--including five found via the Internet--who had overlapping deletions of genetic material from chromosome 3. This narrowed the search to one part of that chromosome. Although the implicated region contained an estimated 15 genes, two were likely candidates. ZIC1, short for Zinc finger in cerebellum 1, was a known gene that played a role in development of the cerebellum in mice. ZIC4 was previously uncharacterized but was similar to ZIC1.
When the researchers generated mice with altered ZIC1 and ZIC4 genes they found a syndrome virtually identical to the human disorder. Mice with one dysfunctional copy of either gene had mild anatomic abnormalities but no behavioral changes. But about 15 percent of the mice that had one normal and one abnormal version of both ZIC1 and ZIC4 had abnormalities in the cerebellum that were very similar to the brains of patients with Dandy-Walker. They also lacked coordination and were unable to right themselves if they fell over.
Although the authors conclude that "heterozygous loss of ZIC1 and ZIC4 is the cause of Dandy-Walker malformation in deletion 3q2 patients," they caution that other genes are clearly involved, which is why only 15 percent of the mice with the characteristic deletions had severe symptoms. "The genetics of Dandy-Walker are very complicated," said Dr. Millen.
"We still don't know all we want to know about this disorder," added Dobyns, "but now we have a foot in the door for understanding this and other cerebellar defects."
A genetic test could improve prenatal diagnosis. Currently, detecting Dandy-Walker with ultrasound images is difficult and often uncertain until late in a pregnancy, usually after 20 weeks. Most parents, fearing mental retardation, choose to terminate the pregnancy if the disorder is diagnosed soon enough. A reliable genetic test could provide better information earlier and could be used to reassure parents that a subsequent pregnancy was normal.
The story of Dandy-Walker malformation has come full circle, note the authors. The name comes from the physicians Walter Dandy of Johns Hopkins, and Earl Walker, who was a neurosurgeon at the University of Chicago in 1942 when he described the malformation that was subsequently named after him.
"Finding these genes here at the University of Chicago is a kind of 'coming home' story," Millen said.
The National Institutes of Health, the Brain Research Foundation of Chicago, and the Ragins-Goldsmith Fund supported the research. Additional authors include Hope Northrup of the University of Texas, Holly Ardinger of the University of Kansas, and Chitra Prasad of the London Health Sciences Center, of Ontario, Canada.