Background: The Repeat Expansion Diseases are caused by the intergenerational expansion of a specific tandem repeat. Expansion of a CGG.CCG-repeat in the 5'UTR of the FMR1 gene is associated with 3 different clinical presentations: Individuals with 55-200 repeats, so-called premutation alleles, are at risk for Fragile X-associated tremor-ataxia syndrome (FXTAS). In addition to symptoms resulting from cerebellar degeneration, individuals with FXTAS can have a late-onset dementia, elevated risk of diabetes and hypothyroidism, as well as bowel and urinary incontinence. Female carriers of premutation alleles are also at risk of primary ovarian insufficiency (FXPOI). Since the carrier frequency of these alleles is 1/250 these may be significant public health issues. In addition to these problems, the premutation allele can undergo further expansion on maternal transfer resulting in alleles with >200 repeats. Individuals who inherit these so-called full mutation alleles almost always have Fragile X mental retardation syndrome (FXS), the most common cause of mental retardation and the most common known cause of autism. The molecular basis of the pathology seen in premutation carriers is not known, but since the levels of the FMR1 gene product, FMRP, are significantly higher than full mutation carriers who do not have such symptoms, it is thought that the FMR1 mRNA itself is somehow responsible. Data, from my group (Handa, Saha and Usdin, 2003) and elsewhere, do support the idea that RNA with a large CGG-repeat tract is deleterious. Progress report: We previously generated FX premutation mice containing 120 CGG.CCG-repeats in the 5 UTR of the endogenous murine Fmr1 gene (Entezam et. al., 2007). Like humans with the same number of repeats, these mice produce elevated levels of Fmr1 mRNA. These mice also show pathological changes reminiscent of those seen in human carriers of premutation alleles. They show signs of neurodegeneration and ovarian abnormalities that suggest that these animals will be suitable for studying the repeat-mediated RNA pathology thought to be responsible for both FXTAS and FXPOI. We have shown that the ovaries of premutation mice differ in a number of ways from the ovaries of WT animals and that these differences probably reflect problems intrinsic to the ovary rather than problems arising elsewhere in the Hypothalamic-Pituitary-Gonadal axis. This is consistent with our finding that the Fmr1 gene is expressed very highly in the cells of the ovary particularly in oocytes at all stages of maturation. Surprisingly, unlike what has been seen in the brains of individuals with FXTAS and what we have observed in the brains of our FX premutation mice, no intranuclear inclusions are seen. Whether ovarian and brain pathology share a common mechanism is unknown. However, our data suggests that at least in ovary, inclusion formation does not contribute to pathology. A number of clues as to the underlying problem are currently being further investigated.

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Iliff, Adam J; Renoux, Abigail J; Krans, Amy et al. (2013) Impaired activity-dependent FMRP translation and enhanced mGluR-dependent LTD in Fragile X premutation mice. Hum Mol Genet 22:1180-92
Hoffman, Gloria E; Le, Wei Wei; Entezam, Ali et al. (2012) Ovarian abnormalities in a mouse model of fragile X primary ovarian insufficiency. J Histochem Cytochem 60:439-56
Qin, Mei; Entezam, Ali; Usdin, Karen et al. (2011) A mouse model of the fragile X premutation: effects on behavior, dendrite morphology, and regional rates of cerebral protein synthesis. Neurobiol Dis 42:85-98