INSTABILITY OF A 550 BASE PAIR DNA SEGMENT AND ABNORMAL METHYLATION IN FRAGILE X-SYNDROME
INSTABILITY OF A 550 BASE PAIR DNA SEGMENT AND ABNORMAL METHYLATION IN FRAGILE X-SYNDROME
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DOI：
10.1126/science.252.5009.1097
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发表时间：
1991-05-24
期刊：
影响因子：
56.9
通讯作者：
MANDEL, JL
中科院分区：
文献类型：
--
作者：
OBERLE, I;ROUSSEAU, F;MANDEL, JL
脆性 X 综合征是遗传性智力低下的常见原因，其特点是不寻常的遗传模式。表型表达与位于或非常接近脆弱位点的单个 CpG 岛的异常胞嘧啶甲基化有关。邻近该岛的探针检测到了非常局部的 DNA 重排，这些重排构成了脆弱的 X 突变，其目标是一个 550 碱基对富含 GC 的片段。正常传播的雄性有 150 至 400 个碱基对的插入，这些插入由其女儿遗传，要么保持不变，要么大小有微小差异。下一代脆弱的 X 阳性个体具有更大的片段，这些片段在兄弟姐妹之间有所不同，并且表现出普遍异质的模式，表明存在体细胞突变。突变的等位基因在正常遗传雄性中似乎未甲基化，在其女儿中仅在不活跃的 X 染色体上甲基化，而在大多数脆弱的 X 雄性中完全甲基化。然而，一些雄性有马赛克图案。因此，脆性 X 综合征的表达似乎是两步突变和高度局部甲基化的结果。无论性别或表型表达如何，脆性 X 突变的携带者都可以很容易地被检测到，并且罕见的明显假阴性可能因遗传异质性或误诊而导致。
The fragile X syndrome, a common cause of inherited mental retardation, is characterized by an unusual mode of inheritance. Phenotypic expression has been linked to abnormal cytosine methylation of a single CpG island, at or very near the fragile site. Probes adjacent to this island detected very localized DNA rearrangements that constituted the fragile X mutations, and whose target was a 550-base pair GC-rich fragment. Normal transmitting males had a 150- to 400-base pair insertion that was inherited by their daughters either unchanged, or with small differences in size. Fragile X-positive individuals in the next generation had much larger fragments that differed among siblings and showed a generally heterogeneous pattern indicating somatic mutation. The mutated allele appeared unmethylated in normal transmitting males, methylated only on the inactive X chromosome in their daughters, and totally methylated in most fragile X males. However, some males had a mosaic pattern. Expression of the fragile X syndrome thus appears to result from a two-step mutation as well as a highly localized methylation. Carriers of the fragile X mutation can easily be detected regardless of sex or phenotypic expression, and rare apparent false negatives may result from genetic heterogeneity or misdiagnosis.