Fragile X syndrome and Friedreich ataxia

Diabetes, Digestive, Kidney Diseases

Investigators

Linked publications & trials

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 4 different clinical presentations: Individuals with 60-200 repeats, the so-called premutation, are at risk for 3 different sets of symptoms. Both males and females show a high incidence of depression and behavior problems including disinhibition. Older people are also at risk for Fragile X-associated tremor-ataxia syndrome whose symptoms include dementia as well as bowel and urinary incontinence. In addition to these problems female carriers of premutation alleles are at risk of premature ovarian failure. Current thinking is that the RNA with its expanded CGG-repeat tract is somehow responsible for disease pathology. Females premutation carriers are also at risk of having a child with >200 repeats, the so-called full mutation. These individuals have Fragile X mental retardation syndrome (FXS), the most common cause of mental retardation and the most common known cause of autism. Some individuals with FXS also have hyperphagia and obesity. Symptoms result from some combination of repeat-induced gene silencing and difficulties in translating any residual FMR1 mRNA. This results in a deficiency of the protein product of this gene, FMRP, a protein involved in the regulation of translation of certain mRNAs. GAA:TTC-repeat expansion in the first intron of the frataxin gene causes a deficit in frataxin mRNA. This results in a deficiency of frataxin, an essential nuclear-encoded mitochondrial protein of unknown function. This results in Friedreich ataxia, a degenerative disease associated with cerebellar dysfunction, hypertrophic cardiomyopathy, and diabetes. We are interested in both the mechanism of expansion and the consequences of expansion in these disorders. Progress report: We had previously generated FXS premutation mice containing 120 CGG?CCG-repeats in the 5? UTR of the endogenous murine fmr1 gene. Like humans with the same number of repeats, these mice produce elevated levels of fmr1 mRNA that recent data, from my group and elsewhere, suggests is toxic. Preliminary studies on the ovaries and brains of these mice shows no gross differences in morphology even in middle age. However, microarray analysis shows a number of interesting changes in gene expression in the brains of even very young mice. The intergenerational instability of the repeat in our FXS premutation mice is very high, with a bias, as in humans, for expansions. Large expansions into the full mutation range occur at low frequency. The detection of even this low frequency of expansion is important since these are the only examples of the intergenerational expansion of a repeat into the full mutation in a mouse model for any of the Repeat Expansion Diseases. More importantly, similarly sized alleles are extremely difficult to generate by conventional gene targeting strategies. Thus these mice give us a unique opportunity to directly examine the effects of this expansion. Early analysis of these animals is promising. While they do not show the aberrant DNA methylation seen in most humans with the full mutation, they do show the same difficulties in translating mRNA from alleles with large numbers of repeats. As a result they make little if any FMRP. Thus they might be good models for that large group of humans with the full mutation who still make significant amounts of FMR1 mRNA. As part of a larger effort to explore ways of ameliorating the FMR1 deficiency in those with FXS we have characterized the promoter of a gene, FXR2, whose function is thought to overlap with FMR1. We are also in the process of testing various small molecules that are able to reactivate or upregulate other genes to increase transcription of FXR2, FMR1 and frataxin. As part of an ongoing effort to understand the molecular basis of the effects of the FXS RNA we have shown that the repeat responsible for another disorder that is also thought to result from RNA pathology, spinocerebellar ataxia type 10, like the FXS repeat, also forms RNA hairpins. Thus hairpin formation is a conserved property of all of the RNA repeats that are thought to be pathological. This conserved property suggests possible mechanisms for disease pathology that are currently being tested.