Mutations of a single gene, fragile X mental retardation 1 (FMR1), give rise to a family of disorders occurring throughout the entire life span, including the most common heritable form of intellectual disability, fragile X syndrome, and premature menopause (primary ovarian insufficiency). Moreover, mutations of FMR1 are the cause of one of the most common single-gene, late-onset neurodegenerative disorders, fragile X–associated tremor/ataxia syndrome (FXTAS). Some clinicians might assume they will rarely if ever encounter one of these disorders; that assumption would be both false and unwise.
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Expression of the fragile X mental retardation 1 (FMR1) gene depends on the length of the CGG repeat. Premutation alleles result in elevated mRNA levels (increased RNA synthesis). Within this CGG repeat range, the expanded CGG repeat in FMR1 mRNA partially blocks translation to an extent that depends on the size of the repeat. Full mutation alleles are generally hypermethylated and silenced, thus producing little or no mRNA or protein. The excess premutation mRNA is now believed to give rise to the premutation-specific disorders, fragile X–associated tremor/ataxia syndrome and primary ovarian insufficiency, and may also contribute to developmental delays, attention-deficit/hyperactivity disorder, or autism spectrum disorders in some children with the premutation. By contrast, fragile X syndrome is caused by the absence of the FMR1 mRNA and protein (FMRP). In the upper portion of the premutation CGG repeat range, mRNA toxicity and reduced FMRP levels may both contribute to clinical involvement. UTR indicates 5′ untranslated region.
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