The FMR1 gene is a segment of DNA that provides instructions for brain development. It is located on the X chromosome. Understanding its function and variations helps comprehend related genetic conditions.
The Role of the FMR1 Gene
The FMR1 gene produces Fragile X Messenger Ribonucleoprotein (FMRP), a protein found in various bodily tissues, including the brain, testes, and ovaries. FMRP plays a significant role in the development of connections between nerve cells, called synapses.
FMRP regulates synaptic plasticity, the ability of synapses to change and adapt over time, which is important for learning and memory. The protein transports messenger RNA (mRNA) and controls protein production, essential for the proper functioning of nerves, testes, and ovaries.
FMR1 Gene Mutations
A specific region within the FMR1 gene contains a DNA segment known as a CGG trinucleotide repeat. This sequence is repeated multiple times, and the number of repeats classifies the FMR1 gene.
The normal range is 5 to 44 CGG repeats. These alleles are generally passed from parent to child without significant changes in repeat size.
An intermediate, or “gray zone,” allele has between 45 and 54 CGG repeats. Individuals in this range typically do not experience symptoms, but there is a slightly increased likelihood for the repeat count to expand in future generations.
A premutation occurs when the CGG repeat count falls between 55 and 200. The gene in this state is unstable and can lead to specific medical conditions in carriers. When a premutation is passed from a mother to her children, there is a substantial risk that the number of CGG repeats will expand further, potentially leading to a full mutation.
A full mutation is characterized by more than 200 CGG repeats. When the repeat count reaches this level, methylation occurs in a regulatory region of the FMR1 gene. This methylation effectively “turns off” or silences the gene, preventing it from producing the FMRP protein.
Conditions Caused by FMR1 Mutations
Mutations in the FMR1 gene are linked to a spectrum of conditions, with the specific type of mutation determining the resulting health impacts. The absence or reduction of the FMRP protein, or the presence of unstable mRNA, underpins these disorders.
Fragile X Syndrome (FXS)
Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability and is primarily caused by a full mutation of the FMR1 gene. Individuals with FXS often experience a range of developmental delays, including slower progress in sitting, crawling, walking, and speech. Intellectual disabilities can vary from mild learning difficulties to more severe impairments. Behavioral characteristics may include anxiety, attention-deficit/hyperactivity disorder, autism spectrum disorder features, poor eye contact, and repetitive behaviors such as hand flapping. Distinct physical features, such as a large head, long face, prominent forehead and chin, protruding ears, and larger testes after puberty, may also be present, particularly in males.
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder that typically affects older adults, predominantly males, usually after age 50. This condition is caused by an FMR1 premutation. Key symptoms include intention tremors, which are involuntary shakiness that occurs during voluntary movements like reaching for an object. Balance problems, known as ataxia, also commonly develop and can progressively worsen. Cognitive decline, including short-term memory loss and difficulties with executive functions such as planning and problem-solving, is also observed. Some individuals may also develop parkinsonism, characterized by resting tremors, rigidity, and slowed movement. Researchers believe that high levels of FMR1 mRNA, produced from the premutation, are toxic and contribute to the cellular injury seen in FXTAS.
Fragile X-associated Primary Ovarian Insufficiency (FXPOI)
Fragile X-associated Primary Ovarian Insufficiency (FXPOI) is another condition linked to the FMR1 premutation, affecting women. This disorder involves a reduced function of the ovaries, which can lead to irregular menstrual cycles, infertility, and early menopause, often occurring before the age of 40. The decrease in ovarian function results in lower levels of estrogen, leading to symptoms commonly associated with menopause, such as hot flashes, insomnia, and bone thinning. While the exact mechanisms are still being studied, the overproduction of abnormal FMR1 mRNA in premutation carriers is thought to contribute to FXPOI.
Inheritance and Genetic Testing
The FMR1 gene is located on the X chromosome, making its inheritance pattern X-linked. This means that the risk of inheriting a mutation differs depending on the sex of the parent carrying the mutation and the sex of the child. Females have two X chromosomes, while males have one X and one Y chromosome.
When a mother carries an FMR1 premutation, there is a 50% chance with each pregnancy that her child, whether a son or a daughter, will inherit the gene mutation. The number of CGG repeats in the mother’s gene is a major factor in determining whether the child will inherit a premutation or a full mutation. The premutation is more likely to expand to a full mutation when passed from a mother to her children.
A father with an FMR1 premutation will pass his X chromosome, and thus the premutation, to all of his daughters. He will not pass the FMR1 gene to his sons, as sons inherit their Y chromosome from their father. When passed from a father to a daughter, the number of CGG repeats typically remains stable and does not expand to a full mutation.
Genetic testing for FMR1 mutations is a specialized molecular process, typically performed using a blood sample. This testing accurately counts the number of CGG repeats in the FMR1 gene and can also assess the methylation status of the gene, particularly for full mutations. Testing may be considered for individuals with unexplained intellectual disability, developmental delay, or autism spectrum disorder. It is also recommended for symptomatic individuals with features suggestive of Fragile X syndrome, a family history of Fragile X-related conditions, or women experiencing unexplained ovarian insufficiency, failure, or elevated FSH levels before age 40.