Disease pathology in the Fragile X-associated disorders

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

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. Recent 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 FXS 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 and suggest that these animals will be suitable for studying the repeat-mediated RNA pathology thought to be responsible for FXTAS. We have now shown that these mice have distinct abnormalities in ovarian histopathology that suggest they may also be good models for the ovarian pathology seen in female carriers of premutation alleles.