X-linked recessive inheritance
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Fragile X syndrome

Fragile X Syndrome is the most common inherited cause of mental retardation, and is associated with autism. more...

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The fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 4000 females.

Normally, the FMR1 gene contains between 6 and 53 repeats of the CGG codon (trinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230 repeats of this codon.

Expansion of the CGG repeating codon to such a degree results in a methylation of that portion of the DNA, effectively silencing the expression of the FMR1 protein.

This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction and fragility of the X chromosome at that point, a phenomenon that gave the syndrome its name.

The mutation and methylation of the FMR1 gene lead to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP binds and facilitates the translation of a number of essential neuronal RNAs. In fragile X patients, however, these RNAs are not translated into proteins. The various sequelae of fragile X syndrome result.

Transmission of the Fragile X

The diagram (above) of X-linked recessive inheritance is not entirely inappropriate but it markedly oversimplifies the situation and does not provide a sufficient foundation for genetic counseling with the fragile X syndrome.

Because males normally have only one copy of the X chromosome, those males with significant trinucleotide expansion at the FMR1 locus are symptomatic. They are mentally retarded and may show various physical features of the fragile X syndrome.

Females have two X chromosomes and thus have double the chance of having a working FMR1 allele. Females carrying one X chromosome with an expanded FMR1 gene can have some signs and symptoms of the disorder or be normal.

Males with the fragile X cannot transmit it to any of their sons (since males contribute a Y chromosome, not an X, to their male offspring.)

Females carrying one copy of the fragile X can transmit it to their sons or daughters. Sons who receive the fragile X are at high risk for mental retardation. Daughters who receive the fragile X may appear normal or they may be mentally retarded, usually to a lesser degree than boys with the syndrome.


Aside from mental retardation, prominent characteristics of the syndrome include an elongated face, large or protruding ears, large testicles (macroorchidism), and low muscle tone. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness and limited eye contact. Some individuals with the fragile X syndrome also meet the diagnostic criteria for autism.

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Gene for inherited retardation found - fragile X syndrome
From Science News, 6/8/91 by Carol Ezzell

Physicians currently diagnose fragile X syndrome -- the most common inherited cause of mental retardation -- by placing a patient's cells under a microscope and scanning for a nearly broken X chromosome whose tip hangs by a flimsy thread. Candidates for the test include not only the mentally retarded but also some healthy individuals who may be "silent carriers," capable of passing the disorder to their children or grandchildren. Unfortunately, the chromosome test spots only 70 to 80 percent of these carriers.

Now, U.S. and Dutch scientists have identified the specific gene involved in fragile X syndrome. Testing for mutations in this gene, they say, should improve physicians' ability to predict whether prospective parents risk having a baby with the disorder.

The researchers -- from Emory University School of Medicine in Atlanta, Baylor College of Medicine in Houston, Erasmus University in Rotterdam and Sylvius Laboratory in Leiden -- dubbed the gene FMR-1, for fragile X mental retardation-1. Although they have not yet discovered the gene's normal function, they note that certain stretches of FMR-1 are duplicated many times over in silent carriers and in patients with fragile X syndrome. The duplications disrupt the gene's message, just as repeating words randomly throughout a sentence would make it unreadable. The investigators presume that this disruption can somehow lead to mental retardation.

"This is an advance," says David H. Ledbetter, a Baylor geneticist not involved in the study. The test for the repeated gene "presents a better diagnostic strategy" than chromosome analysis, he says.

To identify individuals carrying the duplications, the researchers chopped up samples of their genetic material and sorted the bits according to length. People with the fragile X gene had extra-long fragments, a telltale sign of duplications.

"We think that repeat region expands by an amplification mechanism that we don't understand yet," says Stephen T. Warren of Emory, who directed the work. He suggests that the amplification makes the X chromosome more fragile.

Warren and his collaborators note in the May 31 CELL that the gene directs the production of a protein bearing multiple positive electrical charges. Because DNA is negatively charged, the protein encoded by this gene could bind to DNA, perhaps regulating other genes.

An understanding of the protein's action may one day point the way to a strategy for reversing fragile X syndrome, Warren says. This form of retardation affects 1 in 1,000 males and 1 in 2,500 females worldwide. Down's syndrome -- the leading cause of mental retardation -- affects 1 in 600 babies, but subsequent generations cannot inherit it.

Warren's team is now developing a faster screening test, using antibodies to the protein, for routine use in medical laboratories. Only academic medical centers and specialized genetic testing labs are equipped to undertake the complex procedure the researchers used in their study, he says.

COPYRIGHT 1991 Science Service, Inc.
COPYRIGHT 2004 Gale Group

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