Trinucleotide Repeat in Fragile X Syndrome
Trinucleotide Repeat in Fragile X Syndrome Fragile X syndrome is the most common inherited cause of intellectual disability and autism spectrum disorders. At the core of its genetic basis lies a specific type of mutation involving trinucleotide repeats within a particular gene. These repeats are sequences of three nucleotides—cytosine (C), guanine (G), and adenine (A)—that are repeated numerous times in a row. In the case of fragile X syndrome, the FMR1 gene, located on the X chromosome, contains a sequence of CGG repeats that expand beyond normal limits, leading to the disorder.
In healthy individuals, the CGG trinucleotide sequence appears a certain number of times—typically fewer than 55 repeats. This range is considered normal and does not cause any adverse effects. However, when the number of repeats increases beyond this threshold, it begins to interfere with the gene’s normal function. The intermediate range, often called the “grey zone,” involves 55 to 80 repeats, which may sometimes be unstable but usually do not cause symptoms. The premutation range, from about 80 to 200 repeats, is associated with some clinical features, such as fragile X-associated tremor/ataxia syndrome (FXTAS), but does not typically result in the full spectrum of fragile X syndrome. The full mutation, characterized by over 200 CGG repeats, leads to the silencing of the FMR1 gene, resulting in the absence or deficiency of the fragile X mental retardation protein (FMRP). This protein is crucial for normal neural development, and its deficiency underpins the cognitive, behavioral, and physical features of fragile X syndrome.
The expansion of trinucleotide repeats is a dynamic process, often occurring during DNA replication. The larger the number of repeats, the higher the likelihood of further expansion in subsequent generations. This phenomenon explains the phenomenon of genetic anticipation, where symptoms become more severe and appear earlier in successive generations. It also accounts for the high variability of symptoms seen among individuals with fragile X syndrome.
Testing for the number of CGG repeats in the FMR1 gene is a key diagnostic tool. It involves polymerase chain reaction (PCR) and Southern blot analysis, which accurately determine repeat size and detect methylation status—an important factor in gene silencing. Early diagnosis is vital for management, as it allows for tailored educational, behavioral, and medical interventions. Genetic counseling is also recommended for affected families, given the inheritance pattern and the risk of expansion in future generations.
Understanding the role of trinucleotide repeats in fragile X syndrome illustrates how minute changes at the genetic level can have profound impacts on development and cognition. Advances in genetic research continue to shed light on the mechanisms of repeat expansion and offer hope for targeted therapies in the future, possibly addressing the root cause rather than only managing symptoms.
