Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome.
To study the involvement of the FMR-1 gene in the fragile X syndrome, its expression was studied in lymphoblastoid cell lines and leukocytes derived from patients and normal controls.
Localization of the brain-expressed FMR-1 gene to this EcoRI fragment suggests the involvement of this gene in the phenotypic expression of the fragile X syndrome.
The fragile X [fra(X)] syndrome is the most frequent form of inherited mental retardation, and co-segregates with a fragile site at Xq27.3 as well as with insertion of a variable number of trinucleotide repeats in the 5'-end of the FMR-1 gene.
These recombination events were used to define the position of Fmr-1, the murine homologue of FMR1, which is the gene implicated in the fragile X syndrome in man, and that of DXS296h, the murine homologue of DXS296.
This finding confirms that the fragile X phenotype can exist, without amplification of the CCG repeat or cytogenetic expression of the fragile X, and that fragile X syndrome is a genetically homogeneous disorder involving FMR1.
Fragile X syndrome is associated with massive expansion of a CGG trinucleotide repeat within the FMR-1 gene and transcriptional silencing of the gene due to abnormal methylation.
In the case of fragile X syndrome, sequences adjacent to the repeat are methylated in affected individuals and the FMR1 gene is transcriptionally inactive.
The results described here indicate that some "nonpenetrant" carrier males may have varying amounts of methylation of the FMR-1 region, which can result in mild expression of the fragile X syndrome.
The early transcription of FMR-1 gene and the distribution of FMR-1 mRNAs in human fetuses suggest that alterations of FMR-1 gene expression may contribute to the pathogenesis of fragile-X syndrome and especially the mental retardation.