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In this Article

• What is Fragile X syndrome?
• What causes Fragile X syndrome?
• What keeps the FMR1 gene from producing FMRP in Fragile X syndrome?
• Patient Discussions: Fragile X Syndrome - Describe Your Experience
• Fragile X Syndrome Glossary
• Fragile X Syndrome Index

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: 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.

Human cells 101

More than 100 trillion cells make up the human body. Most of these cells contain all the genes and other information needed to "build" a human being. Much of this genetic information is found in the nucleus of the cell, a "control center" that keeps all the material together in one place.

The nucleus stores its genetic material in packages called chromosomes. Most people have 46 chromosomes in each cell-23 from their mother and 23 from their father. After fertilization, the two sets of chromosomes match up to form 23 pairs. The chromosomes in the 23rd pair are called the sex chromosomes, X and Y; they determine a person's sex. Males usually have one Y chromosome and one X chromosome; females usually have two X chromosomes.

Each chromosome is made up of genes. Genes contain the information used by other parts of the cell to make proteins, the body's building blocks. Proteins make up the structure of your organs and tissues; they are also needed for your body's chemical functions. Each protein performs a specific job in different types of cells, and the information for making at least one protein is contained in a single gene.

Genes are made up of various lengths of DNA, which contains four chemicals: adenine (A), guanine (G), cytosine (C), and thymine (T). These chemicals line up like beads on a necklace to form strands of code. They also pair up with each other to form the double strands that are characteristic of DNA.

The gene's chemical code for a protein has two parts: the introduction area (promoter), and the instructions for creating the protein. The instructions for making the protein are inside the cell's nucleus, but the parts that actually make the protein are outside the nucleus. To send the instructions to the protein-producing areas of the cell, the gene "reads" the chemical code and rewrites it into a new form (called messenger RNA). The new form is then sent out of the cell's nucleus to make proteins. But, if either the original code or the new form of the code is incorrect or has missing parts, the cell can't make the correct protein. Without the protein, the body may not develop or function normally.

This is what happens in Fragile X. The FMR1 gene contains too many repeats of one specific sequence, CGG, which is an important part of the promoter region for making FMRP (see the figure below).

The number of CGG repeats affects how the code is read and rewritten into its new form. So when the new form of the code gets to the protein-making areas of the cell, the cell has trouble using it to make FMRP, the protein that is abnormal, missing, or in low amounts in people with Fragile X. The cell either can't use the code, and so makes no FMRP, or tries to use the code and makes abnormal or unusable FMRP.