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 more than 200 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 FMRP disrupts normal functions of nerve cells and, consequently, 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 FMRP. 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.

A trinucleotide repeat expansion in the FMR1 gene increases a woman's risk of developing a condition called fragile X-associated primary ovarian insufficiency (FXPOI). In this condition, the CGG trinucleotide repeat in the FMR1 gene is repeated about 55 to 200 times, which is referred to as a premutation. Women who develop FXPOI may experience irregular menstrual cycles, an inability to have children (infertility), early menopause, and elevated levels of a hormone known as follicle stimulating hormone (FSH). About 16 to 20 percent of women with a premutation have FXPOI, which leads to abnormal menstrual cycles and elevated FSH levels before age 40 and often causes infertility.

For unknown reasons, the premutation leads to the overproduction of abnormal FMR1 mRNA that contains the repeat expansion. Researchers believe that the abnormal mRNA causes the signs and symptoms of FXPOI. It is thought that the mRNA attaches (binds) to other proteins and keeps them from performing their functions. In addition, the repeats make producing protein from the blueprint more difficult, and consequently, some people with the FMR1 gene premutation have lower than normal amounts of FMRP. As a result, they may have mild versions of the physical features seen in fragile X syndrome (described above), such as prominent ears, and may experience emotional problems such as anxiety or depression.

Men, and some women, with an FMR1 gene premutation are at 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.

As in FXPOI (described above), the premutation causes overproduction of abnormal FMR1 mRNA containing the expanded repeat region, and researchers believe that this abnormal mRNA causes FXTAS. The abnormal mRNA has been found in clumps of proteins and mRNA (intranuclear inclusions) that are found in brain and nerve cells in people with FXTAS. Some researchers speculate that the proteins found in the inclusions cannot perform their normal functions, which could lead to the signs and symptoms of FXTAS. Another hypothesis is that the inclusions could cause the death of nerve cells important for movement and mental function. However, the exact role the inclusions play in the development of the disorder is unknown.

The FMR1 gene premutation (55 to 200 CGG repeats) is associated with a variety of neurological problems grouped as fragile X-associated neuropsychiatric disorders (FXAND). Children with a premutation can have learning disabilities, attention-deficit/hyperactivity disorder (ADHD), intellectual disability, or developmental disorders that affect communication and social interaction (such as autism spectrum disorder). Some adults with a premutation have emotional or psychiatric problems, such as depression, anxiety, obsessive compulsive disorder, extreme tiredness (fatigue), chronic pain, or difficulty sleeping (insomnia). It is estimated that approximately half of people with a premutation have one or more of these problems. The neuropsychiatric abnormalities are thought to be caused by an abundance of abnormal FMR1 mRNA that impairs the function of other proteins.