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. For example, we have shown that these mice have abnormalities in brain structure and function that suggest that these animals will be suitable for studying FXTAS (Entezam et al., 2007;Qin et al, 2011, Iliff et al, 2013). We have also shown that these animals have ovarian abnormalities that suggest that they will also be useful for studying FXPOI (Hoffman et al, 2013). For example, a premature decline in follicle number is seen in the ovaries of these animals. This decline affects gonadotrophin-independent and the gonadotrophin-dependent follicle classes equally. This suggests that dysfunction may reflect problems intrinsic to the ovary rather than problems arising elsewhere in the Hypothalamic-Pituitary-Gonadal axis. Surviving follicles show a reduced number of granulosa cells per follicle as well as zona pellucida abnormalities. Ubiquitin levels are also higher than normal in the oocyte and FMRP shows an abnormal intranuclear localization. Microarray analysis also demonstrates that the expression of a variety of genes is abnormal. Work is in progress to understand how these abnormalities may contribute to the pathology seen in human premutation carriers.

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