Ritchie R J, Knight S J, Hirst M C, Grewal P K, Bobrow M, Cross G S, Davies K E
Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK.
Hum Mol Genet. 1994 Dec;3(12):2115-21. doi: 10.1093/hmg/3.12.2115.
Three fragile sites, FRAXA, FRAXE and FRAXF lie in the Xq27-28 region of the human X chromosome. The expression of FRAXA is associated with the fragile X syndrome, the most prevalent form of inherited mental retardation whilst the expression of FRAXE is associated with a rarer and comparatively milder form of mental handicap. Both the FRAXA and FRAXE sites have been cloned and the fragile site expression found to be due to the expansion of analogous CGG/GCC trinucleotide repeat arrays. We describe here the cloning of the third fragile site, FRAXF, and demonstrate that it involves the expansion of a (GCCGTC)n(GCC)n compound array. PCR analyses across the repeat of normal individuals show that the number of triplets in the array ranges from 12-26 and the most common allele consists of 14 triplet units. Sequencing analyses show that 95% of normal individuals have three copies of the GCCGTC motif and in these individuals, the size variation observed by PCR is due to copy number alterations in the GCC array. In a cytogenetically positive male with developmental delay, the array is expanded by > 900 triplets and the adjacent CpG-rich region is methylated. The array is also expanded in cytogenetically positive carrier females from the family originally used to define the FRAXF site. We conclude that the expanded array corresponds to the FRAXF fragile site.
三个脆性位点，FRAXA、FRAXE和FRAXF位于人类X染色体的Xq27 - 28区域。FRAXA的表达与脆性X综合征相关，这是遗传性智力迟钝最常见的形式，而FRAXE的表达与一种较罕见且相对较轻的智力障碍形式相关。FRAXA和FRAXE位点均已被克隆，并且发现脆性位点的表达是由于类似的CGG/GCC三核苷酸重复序列阵列的扩增。我们在此描述第三个脆性位点FRAXF的克隆，并证明它涉及(GCCGTC)n(GCC)n复合阵列的扩增。对正常个体重复序列进行的PCR分析表明，阵列中三联体的数量范围为12 - 26个，最常见的等位基因由14个三联体单位组成。测序分析表明，95%的正常个体具有三个GCCGTC基序拷贝，在这些个体中，PCR观察到的大小变异是由于GCC阵列中的拷贝数改变。在一名患有发育迟缓的细胞遗传学检测呈阳性的男性中，该阵列扩增了超过900个三联体，并且相邻的富含CpG的区域发生了甲基化。在最初用于定义FRAXF位点的家族中，细胞遗传学检测呈阳性的携带者女性中该阵列也发生了扩增。我们得出结论，扩增的阵列对应于FRAXF脆性位点。
