What is the Cause of Fragile X Syndrome?

Fragile X syndrome is a genetic condition which is caused by a change in a gene that is inherited at the time of conception. This gene, called the FMR1 gene is found on the X chromosome. When this gene change occurs the FMR1 gene does not work properly. The FMR1 gene is responsible for making a protein that is important in brain development. Therefore when the gene is not working properly brain function including learning, behavior and communication is affected. The following paragraphs describe this gene change in great detail.

Cells, Chromosomes, Genes, and DNA

The Fragile X gene can be passed on in families by and to people of either gender who have no obvious signs of FXD. To understand how this happens, we will review basic hereditary information.

Every person’s body is made up of many millions of tiny structures called cells. Within each cell is the genetic information we inherit from our parents. The genetic information is contained in “genes,” and the genes are found lined up on structures called chromosomes. The genes are made from long strands of DNA (deoxyribonucleic acid). DNA is often called the “genetic code.” The DNA molecules are symbolized by letters C, G, T and A.

Each gene is made from a specific sequence of DNA molecules.

Chromosomes and genes are like strings of plastic beads. The whole strand of beads represents the chromosome, each bead might represent a gene, and the plastic from which the beads are made would be the DNA molecules.

Genes, which usually occur in pairs, are the instructions that determine our growth, development, and many other characteristics. For example, certain genes determine eye and hair color, while others determine blood type.

Genes are often called the units of heredity because the information they contain is passed from one generation to the next. We all inherit one gene of each pair from our mother and the other gene in a pair from our father. In this way, our bodies work with a combination of instructions inherited from both our parents. Parents have no control over which genes they pass on to their children.

A given gene can occur in many alternative forms called alleles. For example, the gene for eye color has an allele for blue eyes, an allele for brown eyes, green eyes, etc. This is similar to the various types of apples that occur: each type, such as Delicious, Pippin or Fuji, might be called an allele in the apple family. This concept of each allele as one form of a gene is important in understanding the genetics of FXD, because we all have different size Fragile X alleles.

Thousands of genes pack together to form chromosomes. Most people have 46 chromosomes (23 pairs). There are 44 “non-sex” chromosomes, numbered in pairs from 1-22, that are the same in males and females. We call the 23rd pair the “sex” chromosomes because they determine a person’s sex (male or female). In females, both sex chromosomes are similar and are called “X” chromosomes. Males have one “X” and one “Y” chromosome. The Fragile X gene is on the “X” chromosome. The following diagrams illustrate chromosomes from a female and a male.

The Fragile X Gene—FMR1

Fragile X got its name because under a microscope, a portion of the X chromosome from an individual with fragile X syndrome appears “broken” or “fragile.” As researchers studied this area of the X chromosome in individuals with fragile X syndrome, they found it contained more than the normal amounts of DNA. Specifically, it turned out to have a large number of repetitions of DNA called a CGG repeat. This expansion of DNA is what gives the Fragile X chromosome its unique appearance.

In May 1991, researchers identified the gene responsible for Fragile X. This gene, which is on the X chromosome, is called FMR1, which stands for “Fragile X Mental Retardation 1.” (Note that most of the disability community no longer uses the term “mental retardation,” instead referring to it as “intellectual disability,” but that is what the gene was originally named in the scientific literature.) Every person has at least one copy of the FMR1 gene. Women have two X chromosomes, so they have two copies of the gene. Men have only one X chromosome, so they have just one copy of FMR1. The gene varies in length from one person to another. The variation occurs because there is a range of CG repeat numbers from person to person. What distinguishes people who have a Fragile X mutation from those who don’t is the number of times this CG pattern is repeated. 

Most of our genes either make a protein or regulate proteins made by other genes. The FMR1 gene is responsible for producing a protein that is important in brain development. This protein is called FMRP (Fragile X Mental Retardation Protein). Individuals with fragile X syndrome have a deficiency of this protein.