FMR1 Gene Mutation: Causes, Symptoms, and Inheritance

The FMR1 gene provides instructions for building the Fragile X Messenger Ribonucleoprotein (FMRP). This protein is most concentrated in the brain and is a component of normal cognitive development. FMRP is necessary for synaptic plasticity, the process where nerve cell connections adapt based on experience, which is fundamental to learning and memory. FMRP functions as a transport molecule, carrying messenger RNA (mRNA) to locations where proteins are assembled. By binding to specific mRNAs, it helps regulate the production of other proteins involved in brain function.

The Role of CGG Repeats

The FMR1 gene contains a repeating DNA sequence where cytosine, guanine, and guanine (CGG) are repeated multiple times. The number of these CGG repeats determines the gene’s function. Scientists classify the number of repeats into four categories, each with different health implications.

A normal FMR1 gene has fewer than 45 CGG repeats. In this state, the gene functions correctly, producing the necessary amount of FMRP. An intermediate or “gray zone” range is between 45 and 54 repeats. Individuals in this range do not show symptoms, but the gene is less stable, and the number of repeats could expand when passed to children.

When the number of repeats is between 55 and 200, it is a premutation. The gene is still active but produces an excessive amount of FMR1 mRNA, which can become toxic to nerve cells. This overproduction, rather than a lack of protein, is the source of health issues associated with the premutation.

A full mutation occurs when the CGG segment expands to over 200 repeats. This expansion triggers a process called methylation, which silences the FMR1 gene. This shutdown prevents the gene from producing any FMRP, disrupting the nervous system and leading to the most severe consequences.

Full Mutation and Fragile X Syndrome

The absence of FMRP caused by a full mutation is the direct cause of Fragile X syndrome (FXS). This genetic condition results in a range of developmental and cognitive challenges. The lack of FMRP impairs the development and function of the brain’s communication network.

Individuals with Fragile X syndrome often experience intellectual disability, ranging from mild to severe. Developmental delays are common, affecting speech, language, and motor skills. Many also face social and behavioral challenges, including anxiety, attention-deficit/hyperactivity disorder (ADHD), and features of autism spectrum disorder.

Fragile X syndrome is also associated with certain physical characteristics. These can include a long and narrow face, large ears, a prominent jaw and forehead, and flexible fingers. These features may not be apparent at birth but often become more noticeable with age.

Premutation and Associated Conditions

The FMR1 premutation creates a different biological issue where the gene produces excess messenger RNA (mRNA). This overabundance can be toxic to cells, leading to a distinct set of conditions that typically appear later in life. These disorders are not caused by a lack of FMRP but by the effects of the extra mRNA.

One of the primary conditions affecting carriers is Fragile X-associated tremor/ataxia syndrome (FXTAS). This neurodegenerative disorder primarily affects males over age 50. Symptoms include intention tremors (shaking during voluntary movements) and ataxia, which is a loss of balance and coordination. Individuals may also experience cognitive decline and nerve pain.

Female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). This condition affects the ovaries, leading to reduced function, irregular menstrual cycles, and menopause before age 40. The toxic mRNA is believed to interfere with the normal function of ovarian cells.

Individuals with a premutation do not have Fragile X syndrome. However, the premutation is associated with its own spectrum of issues, including anxiety, depression, and attention deficits. The risk of developing FXTAS or FXPOI depends on factors like the specific number of CGG repeats and the individual’s sex.

Inheritance and Genetic Testing

FMR1 mutations follow an X-linked inheritance pattern, as the gene is located on the X chromosome. Both males (one X and one Y chromosome) and females (two X chromosomes) can be carriers of a premutation. The way the mutation is inherited and the risk of expansion to a full mutation differ depending on the parent.

A male carrier will pass his X chromosome to all of his daughters, making them carriers of the premutation. He passes his Y chromosome to his sons, so they cannot inherit his FMR1 mutation. When a male passes on the premutation, the number of CGG repeats remains stable.

For female carriers, the pattern is different. A female has a 50% chance of passing the affected X chromosome to each child. When a female carrier passes on the gene, the CGG repeat segment is unstable and can expand into a full mutation in the next generation.

Genetic testing can determine an individual’s FMR1 status by measuring the number of CGG repeats. Carrier screening is available for adults planning a family or who have a family history of FMR1-related conditions. Diagnostic testing can also be performed during pregnancy or after birth.