By the time a toddler is 3 or 4 years old, its parents may bewondering whether their child isn't a bit slow learning to talk _ infact in learning altogether.

About one in 1,500 little boys and one in 2,500 little girls owe suchcognitive inabilities to an inherited disorder known as Fragile Xsyndrome. Next only to Down's syndrome, Fragile X is the leadingspecific cause of mental retardation in all countries, and in all ethnicgroups, where such childhood conditions are monitored.

It owes its name to the fact that the fragile X gene clings tenuously tothe extreme tip of the human X chromosome's long arm. No oneknows for sure what the FMR1 gene or its protein product, FMRP,do, but when it mutates, two events conspire to degrade certain brainfunctions and debase intellect.

In the first place, mutation of that 38,000-base-pair FMR1 sequencesets off a concatenation of DNA repeats, in which the non-codingtriplet CGG _ cytosine-guanine-guanine _ expands many times,increasingly with each passing generation.

"Most people agree they are dangerous from beyond the cutoff of thenormal range, 54 or 55 repeats," said molecular geneticist FrancoisRousseau.

Then, adding injury to this insult, he added that for these repeats tobecome pathogenic, "the mutated gene must be inactivated bymethylation." Methyl groups (of the chemical radical _CH3) attachto the gene, making it invisible to the enzymes that produce RNA andthen proteins."

Why Fragile X Boys Outnumber Girls

Methylation, Rousseau observed, "is the same mechanism thatinactivates one of the two X chromosomes in a human female'sgenome." This helps explain why fewer girls than boys inherit theFragile X syndrome.

But it also underlines a concomitant phenomenon, Rousseau toldBioWorld Today: "One in 260 women is a carrier of the mutantFMR1 [the acronym stands for Fragile X Mental Retardation], whichshe passes on to a Mendelian proportion of her progeny." Rousseau ison the medical faculty at Laval University in Quebec City.

He and cellular biologist Edouard Khandjian are principal co-authorsof a paper in the January issue of Nature Genetics, titled: "The fragileX mental retardation protein is associated with ribosomes."

"It has never been shown before," Khandjian told BioWorld Today,"that ribosomes are in any way implicated in any human hereditarydisease. In this paper," he added, "for the first time, we have shownthat that there is in humans a defect in the protein factory'smachinery, and that the defect is inherited."

Ribosomes, which "read" the RNA translation code, aresimplistically described as complexes in the cytoplasm of cells whereRNA comes in one end and tailor-made proteins emerge at the other.They're also pictured as the gizmo that slides along a zipper, unitingits two rows of teeth.

Khandjian described ribosomes as "composed of two subunits of coreproteins, one large, one small. The small subunit consists of about 40polypeptides; the large one of 60 to 70."

He and his co-authors tracked the FMRP protein to proximity withribosomes in several human cell lines and fresh neuronal cultures.They discovered it sitting atop that dual core protein structure. Then,when they washed those ribosomes with special solvents, the fragileX protein product fell off.

"This is a very good indication," Khandjian pointed out, "that thatprotein is not an integral part of the structure." Rather, he surmises,"It looks like one more of the numerous ribosomal factors alreadyknown that are in loose association with ribosomes."

It's a long way from this molecular insight to an understanding ofhow fragile X causes mental retardation. Khandjian, Rousseau andtheir team _ who conduct research at Laval University's teachinghospital of St.-Francois d'Assise in Quebec City _ had started onthat road by surveying expression of the normal FMRP product invarious tissues of the mouse.

Brain Needs More FMRP Than Muscle

"We found," Khandjian said, "that the highest expression is in thebrain. Its neurons express 100 times as much of it as muscle cells. Weknow," he added, "that neurons are filled with ribosomes, whichmeans that they are synthesizing proteins nonstop for maintenance ofneuronal activity."

In their paper, they "propose that fragile X mental retardation mightresult from defects in the translation machinery, due to the absence ofFMRP."

Next, said Rousseau, "We'll be needing animal models to try tofigure out when the protein is crucial for higher cognitivedevelopment. Is it early, during embryogenesis? Or duringchildhood? Is there any hope for any kind of therapy given tochildren already born?" He answered these rhetorical questions byobserving: "If the damage is already done during embryogenesis, theusefulness of any therapeutic intervention will probably be limited."

In furtherance of this line of inquiry, Khandjian is planning to makesome knockout and transgenic mice "and to see the effect ofknocking out the FMR1 gene on the behavior and biology of themouse."

Apropos, he noted that "the protein and the gene are not vital,because you have fragile-X persons 70 and 80 years old. It onlyaffects their intellectual and behavioral functions, not their physicalwell-being."

Rousseau is about to screen 20,000 pregnant women in a pilot projectto identify the one in 260 women in the general population who carrya premutation or mutation, and estimate their risk of having anaffected child." He concluded: "They probably don't know abouttheir condition." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.