Taylor A K, Safanda J F, Fall M Z, Quince C, Lang K A, Hull C E, Carpenter I, Staley L W, Hagerman R J
Department of Pediatrics, University of Colorado Health Sciences Center, Denver 80262.
JAMA. 1994 Feb 16;271(7):507-14.
Fragile X syndrome is caused by a mutation involving expansion of a CGG trinucleotide repeat segment in the fragile X mental retardation-1 (FMR1) gene on the long arm of the X chromosome. This study was undertaken to determine the relative impact of three molecular characteristics of the FMR1 mutation--number of CGG repeats, methylation status, and X inactivation ratio--on the cognitive involvement of female carriers of fragile X syndrome.
Retrospective study with new DNA analysis of known female carriers of fragile X syndrome.
Molecular studies were conducted in a university-based DNA diagnostic laboratory. Patients were originally ascertained through a regional fragile X clinic in a university-affiliated pediatric hospital.
Forty-eight female carriers of fragile X syndrome were studied, including 22 with a premutation (a small expansion to approximately 50 to 200 CGG repeats), 23 with a full mutation (a full expansion to > 200 CGG repeats), and three with both types of mutations (mosaics).
Median IQ score was significantly lower for females with a full mutation than for females with a premutation. No significant relationship was found between IQ score and number of CGG repeats or percentage methylation of the mutant allele within each mutation category. In addition, no significant relationship was found between IQ score and the proportion of normal FMR1 alleles on the active X chromosome in the carrier female group as a whole or in either mutation subgroup. Comparisons of leukocytes and saliva-borne epithelial cells in certain full-mutation carriers revealed striking differences in FMR1 mutation sizes.
Mutation category remains the most important predictor of affectedness in female carriers of fragile X syndrome. Our data do not support use of the proportion of normal FMR1 alleles on the active X chromosome as a predictor of cognitive involvement in female carriers with full mutations. Individual tissue-specific differences exist in the heterogeneous sizes of full mutations and in the presence of premutation/full-mutation mosaicism.
脆性X综合征由位于X染色体长臂上的脆性X智力低下1（FMR1）基因中的CGG三核苷酸重复序列片段扩增突变引起。本研究旨在确定FMR1突变的三个分子特征——CGG重复次数、甲基化状态和X染色体失活比例——对脆性X综合征女性携带者认知功能的相对影响。
对已知的脆性X综合征女性携带者进行新的DNA分析的回顾性研究。
分子研究在一所大学的DNA诊断实验室进行。患者最初是通过大学附属医院的一家地区脆性X诊所确诊的。
对48名脆性X综合征女性携带者进行了研究，其中22名携带前突变（轻度扩增至约50至200个CGG重复序列），23名携带全突变（完全扩增至>200个CGG重复序列），3名同时携带两种类型的突变（嵌合体）。
携带全突变的女性的智商中位数显著低于携带前突变的女性。在每个突变类别中，未发现智商得分与CGG重复次数或突变等位基因的甲基化百分比之间存在显著关系。此外，在整个携带者女性群体或任何一个突变亚组中，智商得分与活性X染色体上正常FMR1等位基因的比例之间均未发现显著关系。对某些全突变携带者的白细胞和唾液来源的上皮细胞进行比较，发现FMR1突变大小存在显著差异。
突变类别仍然是脆性X综合征女性携带者受影响程度的最重要预测指标。我们的数据不支持将活性X染色体上正常FMR1等位基因的比例用作预测全突变女性携带者认知功能的指标。在全突变的异质大小以及前突变/全突变嵌合体的存在方面存在个体组织特异性差异。
