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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Fragile X repeats clog protein synthesis - lack of fmr protein leads to fragile X syndrome - Brief Article
From Science News, 9/3/94 by Richard Lipkin

In fragile X syndrome, as well as several other disorders with genetic components, problems arise because of mutations in the affected cells' genetic codes (SN: 7/10/93, p.20). For some reason, sections of particular genes contain multiple sets of three nucleotides. Typically, 50 sets of these threesomes exist, one right after another. But in aberrant cells, the number of these so-called trinucleotide repeats can exceed 250.

Most of the time, this excessive stretch of DNA repeats never gets transcribed into messenger RNA, and subsequently translated into a protein. But in at least one man with a mild case of fragile X syndrome, the transcription machinery of some cells waded through the gene's threesomes and sometimes even made protein, says Yue Feng of Emory University School of Medicine in Atlanta.

Feng and her colleagues removed samples of cells from this man and grew them in the laboratory. In these, the affected fmr-1 gene had 57, 168, 182, 207, 266, or 285 repeats. The degree to which these genes were abnormal and unable to transfer their information varied depending on the number of repeats. Cells with genes with 182 or more repeats still made messenger RNA, but in reduced amounts. But the protein-building machinery couldn't handle what little RNA existed in cells with 266 or more repeats, she discovered.

These data show for the first time that the lack of fmr protein leads to fragile X syndrome. "He makes some protein but not enough," says Feng. Some researchers have sought ways to trick cells with these altered genes to make messenger RNA. But her results indicate that even then the cell may still fail to make functional protein.

COPYRIGHT 1994 Science Service, Inc.
COPYRIGHT 2004 Gale Group

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