Over 98 percent of cases of the fragile X syndrome are due to dynamic repeat-sequence mutation in the FMR-i gene. The normal, stale repeat sequence consists of CGG triplet repeats interrupted by single AGG trinucleotide sequences. The initial mutation that predisposes the repeat region to become unstable is due to any mechanism that results in an increased number of uninterrupted CGG repeats in the 3' region of the repeat. Factors that affect those mechanisms and factors affecting the subsequent hyperexpansion, eventually leading to the silencing of the gene and consequent mental retardation, have yet to be identified. However, there are intriguing preliminary data that suggest such factors exist. For example, population-based association studies suggest that specific haplotype backgrounds are associated with increased susceptibility of AGG loss. To test hypotheses resulting from these studies, I propose to use sperm from males with specific repeat sequence structures and haplotype backgrounds as an experimental system to examine possible mutation processes and their rates. The results obtained from this detailed analysis of the dynamics of the mutation process will be an important preliminary step to determine the molecular mechanism of this severe mental retardation syndrome.
