Fragile X syndrome (FXS) is a genetic disorder, the most frequent inherited cause of intellectual disability, and the most common single-gene cause of autism spectrum disorder. This condition arises from a genetic issue that affects brain development and function. Signs and symptoms can vary but often include developmental delays, learning disabilities, and social and behavioral challenges. Physical characteristics may also be present, such as a long face, large ears, and flexible joints.
The FMR1 Gene’s Normal Function
The Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene is located on the X chromosome. It holds the instructions for creating a protein called FMRP, which is important for brain development. FMRP aids in the development of connections between nerve cells, known as synapses, which are necessary for learning and memory.
The FMRP protein regulates the synthesis of other proteins at the synapses, ensuring they are made in the correct amounts. In the absence of FMRP, the process of synaptic development and maintenance is disrupted. This disruption underlies the cognitive and behavioral characteristics associated with Fragile X syndrome.
Defining the Trinucleotide Repeat Expansion
The genetic mutation responsible for Fragile X syndrome is a trinucleotide repeat expansion. This occurs within the FMR1 gene where the DNA sequence cytosine-guanine-guanine (CGG) is repeated. In most individuals, this CGG segment is repeated between 5 and 44 times, a range considered normal that allows the FMR1 gene to function correctly.
Some individuals have a repeat number that falls into an intermediate or “gray zone,” between 45 and 54 repeats. While they do not have Fragile X syndrome, the stability of this gene can be less certain. A larger expansion, from 55 to 200 CGG repeats, is classified as a “premutation.” People with a premutation are carriers and do not have FXS but may be at risk for other related disorders, such as Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI).
The full mutation that causes Fragile X syndrome occurs when the number of CGG repeats exceeds 200. This expansion leads to the silencing of the FMR1 gene. The CGG repeat in a premutation allele is unstable and can expand to a full mutation when passed from a mother to her children. This phenomenon, where the severity of a genetic condition increases through successive generations, is known as anticipation.
How the Mutation Silences the Gene
The expansion of the CGG repeat segment beyond 200 copies triggers a biochemical change in the FMR1 gene, a process called DNA methylation. In this process, chemical tags known as methyl groups attach to the DNA in the promoter region of the FMR1 gene, the area that initiates gene activity.
This heavy methylation acts like a switch, turning the FMR1 gene off. The silencing of the gene prevents it from being transcribed into messenger RNA (mRNA), the molecule that carries genetic instructions to the cell’s protein-making machinery. Consequently, the FMRP protein cannot be produced. The resulting deficiency or complete absence of FMRP disrupts normal neurological development.
The timing of this methylation event is specific, occurring around 10 to 12 weeks of gestation. Once silenced, the gene remains inactive, leading to the lifelong consequences of FMRP deficiency. The core issue in Fragile X syndrome is not a flawed protein but the lack of protein production caused by the silencing of a functional gene.
The X-Linked Inheritance Pattern
The FMR1 gene’s location on the X chromosome dictates how Fragile X syndrome is inherited. Because it is an X-linked condition, it affects males and females differently. Males have one X chromosome and one Y chromosome, so a full mutation on their single X chromosome will result in Fragile X syndrome, often with more significant symptoms.
Females have two X chromosomes. If they inherit one X chromosome with the full mutation, they may have a second, normal copy of the FMR1 gene on their other X chromosome. This second copy can often produce some amount of the FMRP protein, leading to a milder presentation of the syndrome. However, some females with the full mutation can still be significantly affected.
The inheritance pattern also explains how the mutation is passed through families. All mothers of individuals with a full mutation are carriers of an FMR1 mutation themselves. When a female with a premutation has children, the unstable CGG repeat can expand into a full mutation during egg formation. Conversely, when a male passes on his premutation, it remains stable in size. This parent-of-origin effect is a distinct feature of the disorder’s inheritance.