SCREEN FOR FRAGILE X MUTATIONS IN PRIMATES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: Fragile X syndrome, the most common inherited form of mental retardation, arises in individuals with more than 200 CGG repeats in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. In humans, approximately 1 in 260 women, is a carrier of the expanded (55 to 200) CGG repeat. We have identified a rhesus macaque pedigree with 3 subject carriers of an expanded CGG region in the premutation range. Human subject carriers of fragile X premutations express higher levels of FMR1-mRNA, between 2 to 10 fold in blood samples. The increased FMR1 expression can lead to cell toxicity over the years and be the cause of Fragile X associated tremor ataxia syndrome (FXTAS) a newly described neurodegenerative disease. It has also been observed that premutation carriers often express lower levels of fragile X protein (FMRP) that presumably causes social phobia, autistic-like behavior, anxiety, OCD, psychotic traits and learning disability. This pedigree represents the first animal model that spontaneously carries an expanded repeat. FMR1 mRNA and protein levels have not yet been analyzed in macaque carriers of premutations (subjects MMU 24660, 34220, 35122). By examining FMR1 gene in this pedigree we expect to make progress in the understanding of the molecular mechanisms leading to the pathological expansion of the CGG repeats in succeeding generations, as well as identifying factors involved in transcriptional-translational regulation.