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Causes of FXS

Fragile X occurs when a mutation in the FMR1 gene stops the body from making FMRP proteins.

FMRP

  • The Fragile X Mental Retardation Protein (FMRP) is found in all cells. However, it is most plentiful in the nerve cells - particularly the part that “talks” to other nerve cells - the dendrites.
  • FMRP in the brain regulates levels of another protein called MGluR5, which 
    tells neurons to grow dendrites and attach to other neurons to pass information along.
  • When the dendrites are the right size and shape, FMRP makes MGluR5 tell the neurons to stop.
  • When FMRP is missing, the dendrites grow uncontrolled and allow signals to get lost on their way from one neuron to another.
  • This makes it hard to learn and respond to stimuli in the same way as people whose neurons can communicate easily.
  • A person with nearly normal levels of FMRP usually has mild FXS symptoms, while a person with very little or no normal FMRP has more severe symptoms.

FMR-1 Gene

  • The FMRI gene has a job to do - creating FMRP.
  • The information for making FMRP involves 2 parts: the introduction or promoter and the instructions for the protein itself.
  • The promoter region of the FMR-1 gene contains repeats of a specific sequence (cytosine-guanine-guanine or CGG) that - when normal - controls the activity level of building FMRP.
  • The FMR-1 gene is found on the X chromosome, which means that girls (with two X chromosomes) have two copies of the FMR-1 gene, and boys (who have one X chromosome) have only one.
  • Girls may be able to compensate for genetic errors if their second copy of FMR-1 is normal, meaning that their fragile X symptoms are generally less severe.

Mutations

  • A mutation is any change in a gene.
  • In the FMR-1 gene, the area of the promoter that is rich in CGG repeats may have a mutation which creates an abnormal expansion of the DNA located there.
  • In a normal FMR1 gene, the CGG pattern appears between 10 - 40 times in a row.
  • In a full mutation of an FMR-1 gene, the CGG pattern can appear more than 200 times causing methylation.
  • This methylation “turns off” the FMR-1 gene so that no FMRP is made.

Premutations

  • Sometimes, the CGG pattern repeats itself more times than normal, but not enough for the full mutation, and not enough to stop the gene from making some FMRP.
  • When this happens, the individual is said to be a “premutation carrier.”
  • The premutation gene can grow into the full mutation in the carrier’s children, grandchildren or descendants - especially when the carrier is female.

Being Mosaic

  • Not every cell in the body is the same. In Fragile X, this means that some cells may have 200 or more CGG repeats in the FMR-1 gene, while other premutation cells may have fewer than 200 repeats.
  • This is called being "mosaic," meaning that the mutation is in some of the cells, but not all of them (or not to the same degree).
  • These premutation cells may be able to make some FMRP resulting in milder  symptoms of Fragile X for mosaic individuals.