Han Xiao-Dong, Powell Berkley R, Phalin Judith L, Chehab Farid F
Department of Laboratory Medicine, University of California-San Francisco, 185 Berry Street, San Francisco, CA 94107, USA.
Am J Med Genet A. 2006 Jul 1;140(13):1463-71. doi: 10.1002/ajmg.a.31291.
The molecular basis in the majority of fragile X patients results from expansion of the CGG repeats in the FMR1 gene causing its transcriptional silencing and deficiency of its encoded protein FMRP. In this communication, we report on a male patient who lacks the characteristic physical features of fragile X and carries a fully methylated mutation, a premutation, a non-methylated full mutation, and a microdeletion encompassing the entire CGG repeat region and 42 bp of upstream flanking sequence. Southern blot analysis revealed that the methylated full mutation accounted for only 10% of his genotype while the premutation/non-methylated full mutation and the microdeletion constituted 37% and 53%, respectively. Immunofluorescent staining of FMRP demonstrated the presence of 22% FMRP in his peripheral blood leukocytes and quantitative RT-PCR revealed a 3.6-fold elevation of FMR1 mRNA levels. Developmental assessments indicated that while he has a learning disability, he does not have mental retardation. Because previous reports had noted that 28% FMRP expression is associated with a characteristic fragile X phenotype, we propose that in our patient the association of 22% FMRP levels with normal physical features and a high-functioning status may have resulted from increased FMRP stability by a mechanism that takes into account the CGG microdeletion and elevated mRNA levels.
大多数脆性X综合征患者的分子基础是FMR1基因中CGG重复序列的扩增，导致其转录沉默以及编码蛋白FMRP的缺乏。在本报告中，我们报道了一名男性患者，他没有脆性X综合征的典型身体特征，携带一个完全甲基化突变、一个前突变、一个非甲基化的完全突变以及一个包含整个CGG重复区域和42 bp上游侧翼序列的微缺失。Southern印迹分析显示，甲基化的完全突变仅占其基因型的10%，而前突变/非甲基化的完全突变和微缺失分别占37%和53%。FMRP的免疫荧光染色显示其外周血白细胞中存在22%的FMRP，定量RT-PCR显示FMR1 mRNA水平升高了3.6倍。发育评估表明，虽然他有学习障碍，但没有智力迟钝。因为之前的报告指出，28%的FMRP表达与典型的脆性X综合征表型相关，我们推测在我们的患者中，22%的FMRP水平与正常身体特征和高功能状态的关联可能是由于一种机制提高了FMRP的稳定性，该机制考虑了CGG微缺失和升高的mRNA水平。
