Focus - September 4th, 1998
Finding Mental Retardation Gene Supports New View of Learning and Memory
By Misia Landau
A gene mutation responsible for a form of inherited mental retardation in
males has been located on the X chromosome, report researchers from Harvard
Medical School and other institutions in the September Nature Genetics. The
discovery offers a new perspective on how neurons interact in learning and
memory because the defect, which causes severe cognitive problems, was found
on a gene that normally regulates neuron shape.
Traditionally, mature neurons were thought to convey messages by changing
their chemical and electrical properties without any change of shape.
"Previously, people had only static pictures--electron micrographs and the
like--and it appeared that the neuron gets set up during development and
that's it," says Christopher Walsh, associate professor of neurology at HMS
and 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 electrical resistance and, in turn, 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 BID and
Children's Hospital, respectively, discovered the new X-linked mental
retardation mutant. As it turns out, the defect, which occurs in the PAK3
gene, is the third mutation for this particular form of X-linked mental
retardation, called nonsyndromic mental retardation (MRX), 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 of any kind. The magnetic resonance image of the brain of
one person carrying the mutant PAK3 appears normal. Yet such gross images
would not reveal defects in cell shape, Walsh says.
In general, the appearance of MRX males is misleading. Despite their
profound behavioral disabilities--delayed and primitive speech as well as
severe learning and social impairments--most of the one in 600 males
affected look remarkably normal. Unlike other forms of retardation, which
entail problems in several organs, MRX appears to affect only the
brain--which is why MRX genes have been so prized by neurobiologists.
Chasing a Different Quarry
Walsh and his colleagues initially thought mutations in PAK3 might be
responsible for a different disorder, called doublecortex. Though their
research ruled that out, they still believed that a PAK3 mutant might cause
some other inherited neurological disease. Allen, who is a
Goldenson-Berenberg postdoctoral fellow at HMS, consulted an international
genetic database and found that four MRX families had mutations mapping to
the region of the X chromosome where PAK3 lies. She found one of the
families carried a PAK3 mutant. The mutation was small--a single base
change. But it turned a normal coding amino acid into a stop codon, the
equivalent of a genetic red light.
Normally, the PAK3 protein consists of two domains--a binding and an
activating domain. In its healthy state, the PAK3 protein acts as a kind of
middleman, shuttling between small G proteins, which it binds, and
cytoskeletal proteins (such as myosin, actin, and microtubulin), which it
activates (see illustration). The stop codon occurred in the middle of the
second, or kinase, domain. When Allen and her colleagues put the defective
PAK3 gene into cultured cells, only the first half of the protein was
functional. The protein showed no kinase activity.
It is not clear exactly how the defective PAK3 protein interferes with the
normal functioning of the nerve cell to cause MRX. One possibility is that
it binds small G proteins but, lacking its kinase domain, is unable to
activate cytoskeletal proteins. "So it hooks up to the G protein but has
nowhere to go because its kinase activity is dead," Walsh says. If so, it
could prevent the small G proteins from doing other things--and small G
proteins typically act as launching sites for a whole series of signal
cascades. "So it could gum up the works," he 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 they will need to know
much more about how PAK3 works before they tinker with kinases or anything
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.