The fragile X syndrome, a type of inherited mental retardation, is due to the silencing of the FMR1 X-linked gene. In over 98% of cases, the mutation is due to an expansion of an unstable CGG repeat sequence located in the 5' untranslated region of the gene. Once over 200 repeats, the FMR1 gene is hypermethylated and consequently no message is transcribed. Based on our previous work and that of others, we have suggested that, in addition to this """"""""full"""""""" mutation, an increased number of CGG repeats may influence an individual's cognitive and behavioral performance. That is, long repeat tracts found among intermediate and premutation alleles (those with 41-199 repeats), although unmethylated, may perturb the transcription/translation machinery or may alter binding properties of other proteins. There is convincing evidence for an underlying molecular etiology related to long repeat tracts in the FMR1 gene, as 21% of women who carry the premutation allele at risk for premature ovarian failure. Given the FMR1 gene is known to play a role in normal brain function, examination of a cognitive and behavioral consequence of FMR1 high repeat alleles is an important next step. In our current grant, we are ascertaining carriers of high repeat alleles to determine if there is a specific neuropsychological profile associated with high repeat alleles, and among women, to further identify specific FMR1-related risk factors associated with ovarian function. In this proposal, we request funds to enhance this comprehensive project by extending the phenotype definition based on current, exciting findings. First, a preliminary study has found that pre-menopausal premutation carriers had high follicle stimulating hormone levels, suggesting that all premutation carriers may have ovarian dysfunction, not only a subset. We propose to determine the hormone profile of high repeat carriers to more accurately define the phenotype related to ovarian function. Secondly, and importantly for both the neuropsychological and ovarian function components, we propose to determine the FMR1 mRNA and FMRP protein levels of high repeat carriers to better define the affect of long CGG repeat tracts. Based on our preliminary studies and those of others, males who carry the premutation have increased levels of mRNA, but decreased levels of FMRP. This exciting finding provides the impetus to apply this newly developed technology to our current study population to increase the power to define the impact of the FMR1 gene on cognitive and behavioral performance and for women on ovarian function.
| Sullivan, A K; Marcus, M; Epstein, M P et al. (2005) Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 20:402-12 |
| Small, Chanley M; Marcus, Michele; Sherman, Stephanie L et al. (2005) CYP17 genotype predicts serum hormone levels among pre-menopausal women. Hum Reprod 20:2162-7 |
