Individuals with a rare inherited disorder called Joubert syndrome are clumsy when they walk or use their hands, and they have irregular breathing and eye movements. Patients with severe symptoms tend to die young.
Scientists have now identified a gene that underlies Joubert syndrome. Christopher A. Walsh of Harvard University and his colleagues found that when the Abelson helper integration site gene (AHI1) on chromosome 6 is abnormal, it disrupts prenatal development of a brain region that controls coordinated movement of hands, feet, and other parts of the body. The finding appears in the September Nature Genetics.
First described 35 years ago, Joubert syndrome affects about 1 in 30,000 people. In 1997, medical experts discovered that patients with the disorder have tooth-shaped lesions in the cerebellum and brain stem. Now, the roots of the disorder are coming to light.
Walsh’s team focused on six children with Joubert syndrome from five families in Saudi Arabia and Turkey. By analyzing DNA from these children and from symptomfree family members and nonrelatives, the researchers tracked down atypical AHI1 genes in the affected children.
Other scientists had identified AHI1 earlier, but its function wasn’t known. Walsh and his colleagues report that the protein encoded by AHI1 is critical to the biochemical process whereby certain nerve cells in the brain grow, branch out across the brain stem, and connect with neurons on the other side of the spinal cord.
When wired to the right partners, these neurons ensure proper muscle control and coordination, Walsh explains. If AHI1 is faulty, however, the neurons fail to cross the brain and instead connect with neurons on the same side. As a result, the feet or hands of Joubert syndrome patients tend to move in the same direction.
When Walsh’s team compared the AHI1 of various mammals, it found substantial differences that pinpointed a portion of the gene as being “particularly dynamic evolutionarily.” Walsh says the discovery of AHI1‘s function could increase scientists’ understanding of how specific brain structures accommodate human motor skills. “We now know that this gene, which hadn’t been suspected of having any role in the brain at all, is essential for so many wiring decisions that affect movement,” he says.
Other genes may contribute to the disorder by disrupting brain development in different ways, Walsh notes. Indeed, several research teams are homing in on additional candidate genes, located on chromosomes 9 and 11.
Moreover, because symptoms vary widely, investigators suspect that additional genes play secondary roles in the disorder. Joubert syndrome sometimes includes mental retardation, autistic behavior, or kidney and liver problems. Melissa Parisi of the University of Washington in Seattle and her colleagues recently reported that a previously known gene deletion on chromosome 2 causes kidney failure in a subgroup of Joubert syndrome patients.
Parisi calls the finding by Walsh’s group an “important discovery” and says that researchers hope many other findings about Joubert syndrome will soon be coming down the pipeline. Such findings, she notes, may lead to prenatal tests to reveal the disorder soon after conception and to better diagnosis and treatment.