Expression of the FMR1 gene.
Fragile X syndrome is a trinucleotide repeat disorder in which a (CGG)n element located within the 5' untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene expands to more than 200 copies (full mutation) and becomes hypermethylated. Such expansions are accompanied by the failure to produce FMR1 protein (FMRP), resulting in the fragile X phenotype. For smaller (premutation) expansions (approximately 55-200 repeats), FMR1 mRNA and FMRP levels had been assumed to be normal; however, our group and others have recently demonstrated that FMR1 mRNA levels are elevated in cells harboring premutation alleles. Moreover, mRNA levels remain elevated in fragile X males with partially methylated full mutation alleles. Finally, some fragile X males with hypermethylated, full mutation alleles continue to produce FMR1 mRNA, despite the expectation that those genes should be silent. These observations all point to a complex mechanism of expression of the FMR1 gene, one that provides a more consistent foundation for the spectrum of clinical involvement. An FMRP deficit is observed in all categories of fragile X individuals, including carriers of the premutation and partially methylated full mutation alleles. These results demonstrate that lowered FMRP levels, in the absence of methylation-coupled silencing of the FMR1 gene, are not caused by reduced transcriptional activity, but rather by a reduced efficiency of translation.
Tassone
F
F
Department of Biological Chemistry, University of California, Davis, School of Medicine, Davis CA, USA. ftassone@ucdavis.edu
Hagerman
P J
PJ
D019175:DNA Methylation; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D012737:Sex Factors; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human