Fragile X Syndrome Flashcards
What kind of genetic disorder is Fragile X?
X-linked and the most common inherited cause of intellectual disability.
What are the two types of FXS?
- Full mutation
- Premutation
Prevalence in Canada?
1/4000 and 1/7000 males and 1/2 as many females.
What causes FXS?
It is caused by decreased or absent levels of fragile X mental retardation (FMR) protein due to a loss-of-function mutation in the FMR-1 gene.
What can we see?
We see a massive CGG expansion, which leads to methylation-coupled silencing of the FMR1 gene, and thus the absence of FMRP.
Difference between full mutation and premutation?
Full: >200 repeats
Pre: 50-200 repeats
How does DNA methylation affect FXS?
DNA methylation occurs on CG(G) repeats (called CpG islands) and causes elongation of CGG repeats, as seen in FXS patients, allowing hypermethylation of the FMR1 gene.
What has an impact on the severity of the FXS phenotype?
Lower levels of FMRP appear to have a major impact on the severity of FXS phenotype.
Where are the highest concentrations of FMRP?
In the brain and testes.
What is the function of FMRP?
It binds to mRNA and transports it out of the cell nucleus into the synapse. (Nucleocytoplasmic shuttling of mRNA)
What does brain tissue from FXS patients show?
Abnormalities in the formation and function of synapses.
What does lack of FMRP cause?
Lack of FMRP reduces mRNA suppression and impairs neuroplasticity (e.g. learning and memory).
Clinical Presentation of FXS?
-Males with full mutation are significantly affected
-Degree of impairment varies widely in females
-Fragile X pre-mutation does not show phenotype (in females)
Presentation in males?
The degree of impairment correlates with the size of the amplification of CGG sites.
Presentation in females?
The degree of impairment in women appears to correlate with the activation ratio of the fragile X chromosome, rather than the size of amplification.
