Infographic: The Genetics of Fragile X Syndrome

The Fragile X Mutation

the scientist staff

Fragile X syndrome is caused by an expansion of CGG nucleotide repeats in the FMR1 gene at the end of the long arms of the X chromosome. To identify the mutation, researchers culture cells in media deficient in folic acid, which causes the ends of the X chromosome to appear as though they are about to break off. Before molecular testing, this was the only way to see the mutation.

The FMR1 gene encodes the fragile X mental retardation protein (FMRP), which regulates gene expression and protein translation in the brain. FMRP is important for maintaining synaptic plasticity and the ability to make new neurons. Levels of FMRP associated with disease severity in patients with FXS.

	Normal CGG repeats < 55	Premutation 55 ≤ CGG repeats ≤ 200	Full Mutation CGG repeats > 200
	Typical	FXTAS, FXPOI, Neuropyschiatric problems	FXS
	Premutation: The FMR1 gene has 55 to 200 CGG repeats that are not methylated. Premutations with fewer than 120 CGG repeats typically lead to normal FMRP levels; more repeats lead to lowered FMRP production, though this doesn’t necessarily translate to more severe disease. Premutations of any number of repeats can result in higher FMR1 mRNA levels, which can cause problems for the individual even if FMRP protein levels are normal. Collectively these problems are referred to as fragile X–associated disorders; they include fragile X–associated tremor/ataxia syndrome (FXTAS), primary ovarian insufficiency (FXPOI), and neuropsychiatric problems.		Full mutation: The FMR1 gene has more than 200 repeats of the nucleotides CGG that are heavily methylated. Males completely lack FMRP, while females typically have some protein produced from the FMR1 gene on the healthy X chromosome. Individuals carrying a copy of the full mutation present with FXS.

Inheritance

In males: Full mutations revert back to premutations during development of X chromosome–carrying sperm. Thus, men with the full mutation or the premutation pass the premutation on to their daughters. Because it is X-linked, they cannot pass it on to their sons.

In females: Premutations of 100 CGG repeats or more convert to the full mutation during egg development or in the embryo. Thus, women with the full mutation or a premutation with 100 repeats or more on one of their X chromosomes pass on the full mutation to their children approximately 50 percent of the time. Women with a premutation of fewer than 100 repeats will pass on a full mutation less often.

Occasionally, if both parents carry premutations or full mutations, their daughters can inherit two fragile X chromosomes: one with a premutation from the father and the other with either a premutation or a full mutation from the mother.

THE SCIENTIST STAFF