MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

超过98%的脆性X综合征病例是由于动态 FMR-i基因中的重复序列突变。 正常的，陈旧的重复 序列由被单个AGG中断的CGG三联体重复序列组成 三核苷酸序列。 最初的突变导致 重复区域变得不稳定是由于任何机制， 在3 '区的不间断CGG重复的数量增加， 重复。 影响这些机制的因素和影响 随后的过度膨胀，最终导致沉默， 基因和随之而来的智力迟钝，还有待确定。 然而，有一些有趣的初步数据表明， 存在. 例如，基于人口的关联研究表明， 特定的单倍型背景与增加的 AGG丢失的敏感性。 为了验证这些假设， 研究中，我建议使用具有特定重复序列的男性精子 结构和单倍型背景作为一个实验系统， 检查可能的突变过程及其速率。 结果 通过对突变动力学的详细分析， 过程将是确定分子的重要初步步骤 这种严重的精神发育迟滞综合征的机制。

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.