Fragile X Syndrome

What keeps the FMR1 gene from producing FMRP in Fragile X syndrome?

The information for making a protein has two parts: the introduction, and the instructions for the protein itself. Scientists call the introduction "the promoter region" of the gene because of its role in starting the protein-building process. (For a more complete description of how proteins are made and the parts of a cell involved in making a protein, see the Human cells 101 section.)

The promoter region of the FMR1 gene contains repeats of a specific sequence (cytosine-guanine-guanine or CGG-see the Human cells 101 section for specific information about the CGG sequence) that, when normal, controls the activity level of the gene in building FMRP.

The number of repeated sequences in the promoter region varies from person to person. Most people who do not have Fragile X have between six and 40 CGG repeats,3 with the average being about 30 repeats in the promoter region.4

However, in a mutated FMR1 gene, the promoter may have hundreds of repeated sequences.

  • A gene with 55 to 200 repeats is generally considered a "premutation."
  • A gene with more than about 200 repeats is called a "full mutation."

The larger number of repeats (more than 200) inactivates the gene. This inactivation process is called methylation. When the gene is inactivated, the cell may make little or none of the needed FMRP.

What goes wrong in a mutated gene?

A number of things can go wrong in a gene that can result in a mutation. The mutation affects the gene's ability to make the needed amount of protein or to make enough usable protein. Some of these mutations include:

Part or all of a gene may be missing.
Chemical sequence of the instructions for making a protein is incorrect.
The promoter region is too big.

In the case of Fragile X, usually the FMR1 gene is present, and its chemical sequence is correct, so neither A nor B apply. However, a mutated FMR1 gene includes repeats of a specific sequence in its promoter region, which creates a mutation like the one shown in situation C.

The number of repeats and their effects are still being studied. At the time this article was printed, the numbers included here were the most commonly cited for premutation in the published scientific literature: Fragile X Syndrome Handbook (2002) National Fragile X Foundation; American College of Medical Genetics Statement: Technical Standards and Guidelines for Fragile X (2001); Rousseau et al. (1996) American Journal of Human Genetics 59(Suppl):A188-1069. However, some research categorizes the premutation differently. For instance, in Crawford et al., 61 to 200 repeats is a premutation, while 41 to 60 repeats is an intermediate mutation (Genetics in Medicine 2001; 3:359-371). The American Academy of Pediatrics Policy Statement. Health Supervision for Children with Fragile X Syndrome uses 50 to 200 repeats for premutation (Pediatrics 1996; 98(2): 297-300). Tassone et al. (American Journal of Medical Genetics 2000; 97[3]:195-203) use large premutation (100 to 200 repeats) and small premutation (55 to 100 repeats). You may encounter differences in the number of repeats for a premutation depending on your source.

One interesting aspect of Fragile X is that, even with a full mutation gene, the body may be able to make some FMRP. Three things affect how much FMRP is produced:

  • The number of CGG repeats. People with a full mutation (200 or more repeats) usually have many of the more severe symptoms associated with Fragile X. In contrast, people with a premutation gene may have few, if any, symptoms and may not even know they carry a mutated gene. Researchers are still trying to sort out any, patterns or trends in the symptoms of people with a premutation gene.
  • Being mosaic. Not every cell in the body is exactly the same. In Fragile X, this means that some cells may have 200 or more repeats in the FMR1 promoter, while other cells, premutation cells, may have fewer than 200 repeats. This is called being "mosaic," meaning either that the mutation is in some of the cells, but not all of them, or that it is not in all of the cells to the same degree. The premutation cells may be able to make FMRP. Similarly, methylation may not happen at all, or to the same degree, in every cell. If enough cells produce FMRP, the symptoms of Fragile X will be milder than if none of the cells produce FMRP.
  • Being female. Because females have two X chromosomes, females with Fragile X have one normal FMR1 gene and one mutated FMR1 gene in most of their cells. But, only one X chromosome is active in each cell, and only the genes on the active chromosome are used to build proteins. The cell seems to randomly choose which chromosome is used. In some cells, then, the X chromosome that contains the normal FMR1 gene is active, and the cell uses it to make FMRP. As a result, even females with a full mutation are often able to make some of the needed protein. For this reason, the symptoms of Fragile X usually affect females less often and less seriously than males.
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