Fragile X syndrome (FXS) is the most common known inherited cause of mental retardation, but it can also manifest as a broad spectrum of behavior and learning problems in individuals with an IQ in the normal range. Preliminary studies have demonstrated less involvement cognitively and physically in fragile X individuals with mosaicism (some cells with a premutation and others with a full mutations) or partial methylation of a full mutation. Our preliminary studies have revealed significant correlations between expression of the FMR1 protein (FMRP) and a) the percent of cells with a premutation in mosaic males and b) the percent of cells with an unmethylated FMR1 gene in males with a full mutation. In females, the percent of cells with the normal FMR1 gene on the active X chromosome (activation ratio) also correlates with the percent of cells producing FMRP. This project will utilize a new technique to measure FMRP expression developed by Dr. Ben Oostra in the Netherlands in addition to FMR1 DNA measures (CGG repeat number, methylation status and activation ratio). These measures will be correlated with clinical measures to investigate fragile X phenotypic variability within the context of a family study format that also accounts for the effects of background genes. This study combines the advances in the statistical modeling of quantitative pedigree data developed by the Australian team, Drs. Loesch and Huggins, with the latest molecular and protein studies to be done in Denver. Nine humdred individuals in 150 families will be evaluated at two centers, Denver and Melbourne, over a three year period. The evaluation includes physical (including anthropometric and dematoglyphic studies), neurocognitive (including executive function measures) and emotional measures which are sensitive to subtle effects of the FMR1 mutation. All molecular and protein studies will be carried out in Denver by Dr. Annette Taylor. This project will characterize whether involvement truly exists in individuals with the premutation and a careful search for subtle mosaicism will be carried out in blood and buccal cells in individuals with the premutation. The project will be a model for investigation of complex genotype-phenotype relationships in other disorders whose genes are now being characteriezed.
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