Gene Mutation Found For Common Form Of Mental Retardation

BOSTON-August 26, 1998--A gene mutation responsible for a form of mental retardation affecting one in 600 males has been located on the X chromosome, researchers from Beth Israel Deaconess Medical Center, Harvard Medical School, and other institutions report in the September Nature Genetics.

Genes for nonsyndromic mental retardation (MRX) have been prized quarry for neurobiologists because unlike other inherited forms of retardation, which involve several organs, MRX appears to affect only the brain. MRX genes therefore give dramatic insight into brain development. The discovery that this defect causes severe cognitive problems, and occurs in a gene that normally regulates neuron shape, gives a new look at how neurons interact in learning and memory.

Traditionally, mature neurons were thought to convey messages by changing their chemical and electrical properties, not by boosting or blocking signals from their neighbors by changing shape. "Previously, people had only static pictures, electron micrographs and the like," says co-author Christopher A. Walsh, a Harvard Medical School researcher at Beth Israel Deaconess.

Using more advanced techniques, researchers have begun to see that electrical transmission is accompanied by movement at the tiny spines located along the neuron's receiving arms, or dendrites. The spines, which accept input from the axons of other nerve cells, appear to contract and expand, increasing or decreasing the ease with which the dendrites conduct electrical impulses.

"So a neuron can sort of tune in one synapse and tune out another by changing the shape of the spine," says Walsh who, with HMS colleagues Kristina Allen and Joseph Gleeson, instructors in neurology at Beth Israel Deaconess and Children's Hospital, respectively, discovered the new X-linked mutant.

As it turns out, the defect, which occurs in the PAK-3 gene, is the third mutation for this form of X-linked mental retardation to be announced in the past three months. Intriguingly, two of the three mutations occur in genes that control cell shape and that may be part of the same signaling pathway in the neuron.

Walsh and his colleagues do not yet know if the newly discovered PAK3 mutation impairs a neuron's ability to change shape, or if it causes physical defects in the neuron of any kind. The magnetic resonance image of the brain of a person carrying the mutant PAK3 appears normal. "Everything is where it should be," Walsh says, but he adds that such gross images would not reveal defects in cell shape. In general, the appearance of males with the MRX defect is misleading. Despite their profound behavioral disabilities, delayed and primitive speech as well as severe learning and social impairments, most look remarkably normal.

Normally, the PAK3 protein consists of two domains, a binding domain and an activating or kinase domain. The mutant form had a defect in the kinase domain. It is not clear exactly how the defective protein interferes with the nerve cell to cause MRX. One possibility is that it is unable to activate the proteins its kinase domain is supposed to trigger. "So it could gum up the works," Walsh says.

This scenario suggests one approach to treating people with MRX would be to target kinases. "If the kinase is dead or partially functional, we might try to boost the activity," says Walsh. Yet he cautions that they will need to know much more about how PAK3 works before they tinker with kinases or anything else.

This research was funded in part by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and the Human Frontier Science Program.