Lugenbeel K A, Peier A M, Carson N L, Chudley A E, Nelson D L
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Nat Genet. 1995 Aug;10(4):483-5. doi: 10.1038/ng0895-483.
Nearly all cases of fragile X syndrome result from expansion of a CGG trinucleotide repeat found in the 5' untranslated portion of the FMR1 gene. Methylation of the expanded repeats correlates with down-regulation of transcription of FMR1; thus fragile X syndrome is postulated to be due to a loss of function of the FMR1 gene product, and this has been demonstrated at the protein level. However, the nature of the mutation offers the possibility of methylation spreading to adjacent genes with consequent loss of expression and contribution to the phenotype. Deletions of FMR1 and flanking sequence (some of substantial size) have been reported in patients with phenotypes consistent with a diagnosis of fragile X-syndrome, however, none is strictly intragenic. We report here the identification of two different intragenic loss of function mutations in FMR1: a single de novo nucleotide deletion in a young male patient (IJ) and an inherited two basepair change in an Adult male (SD), each with classical features of fragile X syndrome.
几乎所有脆性X综合征病例都是由FMR1基因5'非翻译区中发现的CGG三核苷酸重复序列扩增引起的。扩增重复序列的甲基化与FMR1转录下调相关；因此，脆性X综合征被推测是由于FMR1基因产物功能丧失所致，这已在蛋白质水平得到证实。然而，这种突变的性质使得甲基化有可能扩散到相邻基因，从而导致表达丧失并影响表型。在患有符合脆性X综合征诊断的表型的患者中，已经报道了FMR1及其侧翼序列的缺失（其中一些缺失规模较大），但没有一个是严格的基因内缺失。我们在此报告在FMR1中鉴定出两种不同的基因内功能丧失突变：一名年轻男性患者（IJ）中的单个新生核苷酸缺失和一名成年男性（SD）中的遗传性两个碱基对变化，二者均具有脆性X综合征的典型特征。
