FMR1

The FMR1 gene provides instructions for making a protein called fragile X mental retardation 1, or FMRP. This protein is present in many tissues and is found at especially high levels in the brain and testes. In the brain, it may play a role in the development of connections between nerve cells (synapses), where cell-to-cell communication occurs. The synapses can change and adapt over time in response to experience (a characteristic called synaptic plasticity). The fragile X mental retardation 1 protein may help regulate synaptic plasticity, which is important for learning and memory.

Researchers believe that the fragile X mental retardation 1 protein acts as a shuttle within cells by transporting molecules called messenger RNA (mRNA), which contain information for making proteins. Fragile X mental retardation 1 protein likely carries mRNA molecules from the nucleus to areas of the cell where proteins are assembled. It also helps control when the instructions in these mRNA molecules are used to build proteins, some of which may be important for nerve function.

One region of the FMR1 gene contains a particular DNA segment known as a CGG trinucleotide repeat, so called because this segment of three DNA building blocks (bases) is repeated multiple times within the gene. In most people, the number of CGG repeats ranges from fewer than 10 to about 40. This CGG repeat segment is typically interrupted several times by a different three-base sequence, AGG. Having AGG scattered among the CGG triplets appears to help stabilize the long repeated segment.

fragile X syndrome - caused by mutations in the FMR1 gene

Almost all cases of fragile X syndrome are caused by an expansion of the CGG trinucleotide repeat in the FMR1 gene. In these cases, CGG is abnormally repeated from 200 to more than 1,000 times, which makes this region of the gene unstable. As a result, the FMR1 gene is turned off (silenced) and makes very little or no protein. A loss or shortage of the fragile X mental retardation 1 protein disrupts normal functions of the nervous system, causing severe learning problems, intellectual disability, and the other features of fragile X syndrome. About one-third of males with an FMR1 gene mutation and the characteristic signs of fragile X syndrome also have features of autism spectrum disorders that affect communication and social interaction.

Fewer than 1 percent of all cases of fragile X syndrome are caused by other changes in the FMR1 gene. Mutations may delete part or all of the gene or change one of the building blocks (amino acids) used to make the fragile X mental retardation 1 protein. These genetic changes alter the 3-dimensional shape of the protein or prevent any protein from being produced. The abnormal or missing protein disrupts nervous system functions, leading to the signs and symptoms of fragile X syndrome.

other disorders - increased risk from variations of the FMR1 gene

When the CGG trinucleotide repeat in the FMR1 gene is repeated about 55 to 200 times, it is described as a premutation expansion. People with this genetic change do not have the typical signs and symptoms of fragile X syndrome. Most men and women with a premutation expansion are intellectually normal, although some of these individuals have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience emotional problems such as anxiety or depression.

Men, and some women, with a premutation expansion have an increased risk of developing a disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is characterized by progressive problems with movement (ataxia), tremor, memory loss, reduced sensation in the lower extremities (peripheral neuropathy), and mental and behavioral changes. The disorder usually develops late in life and worsens over time.

About 20 percent of women with a premutation have a condition called fragile X-associated primary ovarian insufficiency (FXPOI). These women may have irregular menstrual cycles, an inability to have children (infertility), early menopause, and elevated levels of a hormone known as follicle stimulating hormone (FSH).

Researchers have found that some children with a premutation expansion in the FMR1 gene have learning disabilities, attention deficit hyperactivity disorder (ADHD), intellectual disability, or developmental disorders that affect communication and social interaction (such as autism).