By David N. Leff
As women in the workplace continue to struggle for equality with their male colleagues, it's a fact that genomically the two sexes are unequal — with the score two-to-one in favor of females.
Girls are born with two X chromosomes; boys with only one.
When that single male X chromosome terminates in a labile sequence, severe mental retardation often results. Fragile X syndrome is the second commonest cause of diagnosed mental retardation, after Down's syndrome. And because it's X-linked, Fragile X strikes only boys, afflicting one in 1,000 live births. (See BioWorld Today, Jan. 4, 1996, p. 1.)
"You can take a bunch of boys who are mentally retarded," pointed out neurogeneticist Christopher Walsh, "and separate out those who have the Fragile X syndrome. You can do that clinically, because boys with that form of mental retardation will have certain other signs and symptoms as well. They'll have prominent ears, chins and foreheads, and sometimes large testicles, especially after puberty.
"Also, of course," Walsh added, "you can recognize these kids because when you test their genomes you will see that their X chromosomes have a fragile site."
But in recent decades, neurologists and pediatricians have begun to recognize another form of X-linked mental retardation, with neither the fragility nor those physical symptoms.
"They would see a kid," Walsh continued, "who looked perfectly fine otherwise, but just had low intelligence." This subtle syndrome acquired the name "nonsyndromic X-linked mental retardation" — MRX for short.
Walsh is an associate professor of neurology at Harvard University and chief of neurogenetics at its teaching affiliate, Beth Israel Deaconess Medical Center, in Boston.
"In the most severe cases," he told BioWorld Today, "MRX can be readily recognized as early as two or three years of age by its delayed and primitive speech, as well as gross learning and social impairments. Usually, though, it's not apparent until the kid gets into school. MRX IQs [intelligence quotients] are in the 60 to 80 range — anywhere from borderline to severely retarded.
"The non-syndromic syndrome accounts for one in 600 live births. And it seems to cut across all sorts of ethnic, cultural and racial backgrounds," he said.
As they lack all visible or palpable hallmarks, Walsh pointed out, "these nonsyndromic X-linked mental retardations are generally diagnosed by looking at the patient's entire family. In a single family, you wouldn't recognize it unless you asked about aunts and uncles, and traced the pedigree back a couple of generations. That's not often done," he observed, "for a single kid who goes to a pediatrician.
"The pediatrician may take a while to realize," Walsh went on, "that 'Oh, this kid really has MRX!' And, at that point, he may start quizzing the family very carefully about other affected members. But then, if the same parents had a second defective boy, they would probably recognize it right away. They would know ahead of time that there was a genetic risk."
Walsh is senior author of a paper in the September 1998 issue of Nature Genetics titled "PAK3 mutation in nonsyndromic X-linked mental retardation." It reports the co-authors' hunt for the genetic roots of MRX.
Australians Paved Way To Gene Discovery
"Our work really builds on previous research by a lot of other people who have recognized this MRX syndrome," Walsh pointed out. "Specifically, our co-authors in Australia had found a family with inherited MRX. They analyzed its members' genomes and localized the MRX syndrome to a certain segment of the X chromosome."
To estimate the number of genes on chromosome X, Walsh noted first that it constitutes 10 percent of the human genome — 5,000 to 10,000 X-linked genes. "The Australians had narrowed it down, by DNA-marker analysis, to an area that contained about 10 percent of that — maybe 500 or 1,000 genes," he recounted.
"We happened to be analyzing that portion of the chromosome where they had mapped this disorder," Walsh went on. "So we were able to identify the genes that live in this region, and discovered the PAK gene. It made a lot of sense to us that PAK-3 might be involved in the plasticity of neurons. So we went looking for mutations in that gene, and sure enough we found it in one of four MRX families."
Because nonsyndromic diseases, by definition, lack distinguishing clinical features, MRX can be analyzed for gene mutations in only one family at a time.
In the DNA of that family's members, Walsh and his team found a point mutation on the long arm of chromosome X. But magnetic resonance imaging (MRI) showed no structural deformity of the most severely retarded MRX boy's brain.
"One thing we think really critical," Walsh continued, "is that neurons are covered with little protuberances called spines. They're something like sockets or ports where other neurons can plug in. And by altering the shape of these micro-sockets, you can tune in some of the connections and tune out others. That's where we think the PAK gene comes into play, because it has the ability to alter the shape of these spines.
Neuron 'Spines' Operate Like Computer Ports
"The neuron is like an electrical cell," Walsh explained. "So, altering its shape is like altering the shape of any electrical object. It will change its electrical properties, its resistance, how it works as a transistor, things like that.
"So, it's an amazing biological phenomenon that neurons can change their shape a little bit, and by doing so can alter the source of impulses they are transmitting and the sort of information they are processing.
"One conclusion of our study," Walsh said, "is that implicating this particular PAK gene, especially the kinase enzyme it encodes, suggests some potential therapeutic approaches. People are trying to develop lots of different drugs to stimulate or inhibit kinases.
"The way I think of it," he concluded, "the formation of memory and learning basically requires a certain balance of kinase activity. So, our work offers a potential bridge in trying to tie into that drug-design work, in the hope of actually improving cognitive function. Not just for the small number of specific people who carry that particular MRX mutation in this gene, but probably for the larger population where, by seeing this pathway up close — it's like a chain that can be broken at any link — we might be able to strengthen the whole chain." *