The Gene For Fragile X Syndrome - Medicine and Health

What is the fragile X gene?
The gene responsible for fragile X syndrome is called Fragile X Mental Retardation-1 (FMR1). The FMR1 gene tells the body how to make a protein called Fragile X Mental Retardation Protein (FMRP). Although scientists are still trying to understand its exact function, the FMRP protein is important to the health of nerve cells in the brain.

What goes wrong with the fragile X gene?
A gene is like a recipe for making a protein. The DNA molecules that make up a gene are like the words in a recipe. In one part of the fragile X gene, three "letters" are repeated several times. A few repeats of this sequence doesn't cause a problem, any more than adding a few extra dashes of salt to a recipe would ruin it. Too many repeats, however, creates havoc when a cell tries to "read the recipe." Imagine reading a cake recipe and you see, "add 1 teaspoon of salt" repeated 50 times. Clearly, a cake with that much salt will not taste right. Likewise, repeating a DNA sequence many times over will cause problems.

How does the change happen? The number of repeats can increase if the gene is passed from parent to child. The body makes a copy of each gene before it is passed on. Changes also can occur when the gene is being copied.

How is the change in the fragile X gene passed along?
The FMR1 gene is on the X chromosome. Males inherit one X chromosome from the mother and one Y chromosome from the father. Females get two X chromosomes, one from each parent. If there is a change in an X chromosome gene that could cause a problem, girls have a second X chromosome that almost always carries a normal version of the gene. Boys, on the other hand, do not have a second X chromosome to fall back on. As a result, a boy with too many repeats in the FMR1 gene will get the disease. About half of girls with too many repeats in the FMR1 gene are mentally retarded, but their symptoms are often milder than those of boys.

What are the four classes of fragile X repeats?


Normal: A normal number of repeats ranges from about five to about 40. Within this range, the number of repeats stays the same when the gene is passed on to a child. The child would not have fragile X.
Intermediate: Between 41 and 58 repeats is a "gray zone." Fragile X genes in this range are less stable. When the gene is passed on, the number of repeats may increase, but usually not enough to cause a problem. The child would not have fragile X.
Pre-mutation: When the number of repeats ranges from about 59 to about 200, the gene is in a state of "pre-mutation." The child would not have fragile X, but the number of repeats could increase when the gene is passed on to the child. A female who carries a fragile X gene of this size is at higher risk for premature ovarian failure.
Full mutation: When the number of repeats is greater than 200, the gene cannot work properly. A boy who has a fragile X gene with more than 200 repeats will have fragile X syndrome. A girl with more than 200 repeats may have fragile X, but often with milder symptoms. More than 99% of people with fragile X carry a full mutation. The other 1% probably have another change in the same gene that can’t be detected by routine genetic testing.
Are gene repeats the only change in the gene?
No. There is another change associated with the repeats. When the number of repeats is greater than 200, the gene almost always has another change, called methylation. This means that a chemical group, called a "methyl group," is attached to the gene. With a methyl group attached, the gene cannot work. If the gene is not working in a boy, he will have fragile X. If a girl's FMR1 gene is methylated, she may have fragile X syndrome or she may be protected by a normal FMR1 gene on her other X chromosome.

Methylation causes the most severe symptoms. Knowing the methylation status of the gene helps predict how severe fragile X syndrome will be for a particular person.

A small number of people with fragile X syndrome — less than 1% — do not have a large number of repeats or methylation in the gene. These people have something else wrong with the gene. Routine DNA testing only looks at the number of repeats and methylation. Testing for less common fragile X mutations is offered at a limited number of labs.