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.
These findings demonstrate that FMR1 expression is directly correlated with the fragile X syndrome and suggest that anti-FMR1 antibodies will be important for diagnosis of fragile X syndrome.
Male patients with fragile X syndrome lack FMR1 protein due to silencing of the FMR1 gene by amplification of a CGG repeat and subsequent methylation of the promoter region.
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.
Our results suggest that mutations in FMR-1 are directly responsible for fragile X syndrome, irrespective of possible secondary effects caused by FRAXA.
Our results suggest that mutations in FMR-1 are directly responsible for fragile X syndrome, irrespective of possible secondary effects caused by FRAXA.
In the absence of FMRP, these same mRNAs may be partially translated via alternative mRNPs, although perhaps abnormally localized or regulated, resulting in typical fragile X syndrome.
In the absence of FMRP, these same mRNAs may be partially translated via alternative mRNPs, although perhaps abnormally localized or regulated, resulting in typical fragile X syndrome.
We further suggest that the failure of FMRP to oligomerize, caused by the I304N mutation, may contribute to the pathophysiological events leading to fragile X syndrome.
We further suggest that the failure of FMRP to oligomerize, caused by the I304N mutation, may contribute to the pathophysiological events leading to fragile X syndrome.
Fragile X syndrome is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP), which may play a role in activity-regulated localization and translation of mRNA in dendrites and at synapses.
We conclude that mental retardation associated with the I304N mutation, and likely the Fragile-X syndrome more generally, may relate to a crucial role for RNAs harboring the kissing complex motif as targets for FMRP translational regulation.