Gunter C, Paradee W, Crawford D C, Meadows K A, Newman J, Kunst C B, Nelson D L, Schwartz C, Murray A, Macpherson J N, Sherman S L, Warren S T
Departments of Biochemistry, Pediatrics and Genetics, Emory University School of Medicine and Howard Hughes Medical Institute, Emory University, Atlanta, GA 30322, USA.
Hum Mol Genet. 1998 Nov;7(12):1935-46. doi: 10.1093/hmg/7.12.1935.
In at least 98% of fragile X syndrome cases, the disease results from expansion of the CGG repeat in the 5' end of FMR1. The use of microsatellite markers in the FMR1 region has revealed a disparity of risk between haplotypes for CGG repeat expansion. Although instability appears to depend on both the haplotype and the AGG interspersion pattern of the repeat, these factors alone do not completely describe the molecular basis for the linkage disequilibrium between normal and fragile X chromosomes, in part due to instability of the marker loci themselves. In an effort to better understand the mechanism of dynamic mutagenesis, we have searched for and discovered a single nucleotide polymorphism in intron 1 of FMR1 and characterized this marker, called ATL1, in 564 normal and 152 fragile X chromosomes. The G allele of this marker is found in 40% of normal chromosomes, in contrast to 83% of fragile X chromosomes. Not only is the G allele exclusively linked to haplotypes over-represented in fragile X syndrome, but G allele chromosomes also appear to transition to instability at a higher rate on haplotypes negatively associated with risk of expansion. The two alleles of ATL1 also reveal a highly significant linkage disequilibrium between unstable chromosomes and the 5' end of the CGG repeat itself, specifically the position of the first AGG interruption. The data expand the number of haplotypes associated with FMR1 and specifically allow discrimination, by ATL1 alleles, of single haplotypes with differing predispositions to expansion. Such haplotypes should prove useful in further defining the mechanism of dynamic mutagenesis.
在至少98%的脆性X综合征病例中，该病是由FMR1基因5'端的CGG重复序列扩增所致。在FMR1区域使用微卫星标记已揭示出CGG重复序列扩增的单倍型之间存在风险差异。尽管不稳定性似乎取决于单倍型和重复序列的AGG散布模式，但仅这些因素并不能完全描述正常与脆性X染色体之间连锁不平衡的分子基础，部分原因是标记位点本身的不稳定性。为了更好地理解动态诱变机制，我们在FMR1基因的内含子1中寻找并发现了一个单核苷酸多态性，并在564条正常染色体和152条脆性X染色体中对这个名为ATL1的标记进行了特征分析。该标记的G等位基因在40%的正常染色体中出现，而在脆性X染色体中的比例为83%。不仅G等位基因专门与脆性X综合征中过度出现的单倍型连锁，而且G等位基因染色体在与扩增风险呈负相关的单倍型上似乎也以更高的速率转变为不稳定状态。ATL1的两个等位基因还揭示了不稳定染色体与CGG重复序列本身的5'端之间存在高度显著的连锁不平衡，特别是第一个AGG中断的位置。这些数据增加了与FMR1相关的单倍型数量，并特别允许通过ATL1等位基因区分具有不同扩增倾向的单个单倍型。这样的单倍型在进一步确定动态诱变机制方面应会很有用。
