From the Guidelines
The answer is A. DNA hypermethylation, as it is the primary mechanism responsible for the development of Fragile X syndrome by causing transcriptional silencing of the FMR1 gene. Fragile X syndrome is caused by the deficiency or absence of FMRP, which can occur through any type of deletion or inactivating mutation, but in more than 99% of cases, there is an expansion of a segment of CGG repeats in the 5′ untranslated region of FMR1, leading to hypermethylation and inhibition of transcription 1. This hypermethylation results in the absence or significant reduction of the fragile X mental retardation protein (FMRP), which is essential for normal brain development and synaptic function. The characteristic features of Fragile X syndrome, including intellectual disability, distinctive physical features, and behavioral problems, are a direct consequence of the lack of FMRP due to hypermethylation.
Some key points to consider in the development of Fragile X syndrome include:
- The expansion of CGG repeats in the FMR1 gene is the primary cause of the condition 1
- Hypermethylation of the FMR1 gene promoter region leads to transcriptional silencing and the absence of FMRP 1
- FMRP plays a crucial role in regulating mRNA translation at synapses and is essential for normal brain development and function
- The condition is not caused by truncated or elongated proteins, poly-A shortening, or polyglutamine expansion, which are mechanisms involved in other genetic disorders.
It is essential to note that molecular genetic testing of the FMR1 gene is commonly performed in clinical laboratories to diagnose Fragile X syndrome, and methodological considerations, such as Southern blot analysis and polymerase chain reaction amplification, are crucial for accurate diagnosis 1.
From the Research
Fragile X Syndrome Development
The development of Fragile X syndrome is attributed to several factors, including:
- DNA hypermethylation of the CGG expansion mutation in the 5' UTR of the FMR1 gene 2, 3, 4, 5
- Expansion of the CGG repeat tract to over 200 repeats, leading to epigenetic silencing of the FMR1 gene 3, 4, 5, 6
- Loss of FMRP, a protein important for learning and memory, due to the silencing of the FMR1 gene 3, 5, 6
Key Factors
Some key factors to consider in the development of Fragile X syndrome include:
- The timing of FMR1 hypermethylation and transcription silencing, which is still debated 4
- The role of DNA methylation and other epigenetic modifications in FMR1 gene silencing 5
- The potential for therapeutic strategies to reactivate the FMR1 gene and restore FMRP production 2, 5
Relevant Mechanisms
The relevant mechanisms underlying Fragile X syndrome development include: