CHARACTERIZATION OF THE FRAGILE X MUTATION

Emory University, Atlanta GA

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Abstract

Description: The fragile X syndrome (FXS), a type of inherited mental retardation (MR), 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 (full mutations), the FMR1 gene is hypermethylated and consequently no message is transcribed. Originally, no significant phenotype was thought to be associated with the 6% of individuals in the general population who carry long, unmethylated FMR1 repeat tracks, i.e., those alleles with 41-199 repeats that produce FMR1 mRNA and protein (FMRP). However, there is now convincing evidence for an associated phenotype: 21% of women who carry the premutation allele (6 1-199 repeats) are at risk for premature ovarian failure (POF) while those who carry full mutations have the same risk as the general population. Moreover, preliminary evidence from males indicates that increased levels of FMR1 mRNA and reduced levels of FMRP are associated with increasing repeat number. Based on the applicant?s previous work and that of others, she has suggested that an increased number of FMR1 repeats may influence an individual?s cognitive and behavioral performance. 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. The applicant proposes to determine the FMR1 mRNA and FMRP levels of high repeat carriers to better define the affect of long CGG repeat tracts and associated phenotypes. Specifically, she plans to assess 650 individuals, including high repeat carriers and controls, on whom she has neuropsychological profiles. In addition, she plans to confirm or refute a recent report suggesting that premutation males may be at risk for late onset cerebellar tremors. Lastly, she thinks it is imperative to begin to translate this important genetic information on the FXS, the most common inherited form of MR, into the public health arena. Because women who carry the premutation are not only at risk for having a child with the FXS but also are at risk for POF, she plans to investigate the feasibility of screening women of reproductive age for premutation alleles. This proposal will take the first step to rigorously assess the consequence of high repeat alleles at the molecular and phenotypic level and then determine if these data can be applied at the public health level.