Hirst M, Grewal P, Flannery A, Slatter R, Maher E, Barton D, Fryns J P, Davies K
Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, England.
Am J Hum Genet. 1995 Jan;56(1):67-74.
Screening of families clinically ascertained for the fragile X syndrome phenotype revealed two mentally impaired males who were cytogenetically negative for the fragile X chromosome. In both cases, screening for the FMR1 trinucleotide expansion mutation revealed a rearrangement within the FMR1 gene. In the first case, a 660-bp deletion is present in 40% of peripheral lymphocytes. PCR and sequence analysis revealed it to include the CpG island and the CGG trinucleotide repeat, thus removing the FMR1 promoter region and putative mRNA start site. In the second case, PCR analysis demonstrated that a deletion extended from a point proximal to FMR1 to 25 kb into the gene, removing all the region 5' to exon 11. The distal breakpoint was confirmed by Southern blot analysis and localized to a 600-bp region, and FMR1-mRNA analysis in a cell line established from this individual confirmed the lack of a transcript. These deletion patients provide further confirmatory evidence that loss of FMR1 gene expression is indeed responsible for mental retardation. Additionally, these cases highlight the need for the careful examination of the FMR1 gene, even in the absence of cytogenetic expression, particularly when several fragile X-like clinical features are present.
对临床上已确诊为脆性X综合征表型的家族进行筛查时，发现两名智力受损男性，其脆性X染色体的细胞遗传学检查结果为阴性。在这两个病例中，对FMR1三核苷酸扩增突变进行筛查时，均发现FMR1基因存在重排。在第一个病例中，40%的外周淋巴细胞存在一个660 bp的缺失。PCR和序列分析显示，该缺失包括CpG岛和CGG三核苷酸重复序列，从而去除了FMR1启动子区域和假定的mRNA起始位点。在第二个病例中，PCR分析表明一个缺失从FMR1近端的一个点延伸到基因内25 kb处，去除了外显子11 5'端的所有区域。通过Southern印迹分析证实了远端断点，并将其定位到一个600 bp的区域，对该个体建立的细胞系进行的FMR1 - mRNA分析证实没有转录本。这些缺失患者提供了进一步的确证证据，表明FMR1基因表达缺失确实是智力发育迟缓病因。此外，这些病例凸显了即使在没有细胞遗传学表达的情况下，尤其是当存在几种脆性X样临床特征时，也需要仔细检查FMR1基因。
