Definition
FMR1 is the gene responsible for the production of FMRP .We don't know exactly what the role of FMRP is.
FMRP probably is a RNA-binding protein that is associated to polysomes and may be involved in the transport of mRNA from the nucleus to the cytoplasm. Defects in FMR1 are the cause of Fragile X syndrome, which is a common genetic disease characterized by moderate to severe mental retardation, macroorchidism, large ears, prominent jaw, and high-pitched, jocular speech. The defect in most fragile X syndrome patients results from an amplification of a CGG repeat region which is in 5’UTR untraslated region.
FMRP is involved in normal brain development.
Chemical structure and images
The FMR1 gene contains 17 exons spanning 38 kb.
The molecular weight of FMRP is 71kDa.
Synthesis
The genetic code for how to synthesize FMRP is in the FMR1 (fragile X mental retardation 1) gene on the X chromosome. Males have an X chromosome and a Y chromosome. Males with the stable FMR1 gene on their X chromosome make FMRP. Similarly, males with the premutation make FMRP. But males with the full FMR1 mutation do not make FMRP.
Females have two X chromosomes. That means they have two copies of the FMR1 gene. Females who have the stable FMR1 on both of their X chromosomes make FMRP. Females who have the premutation on one of their X chromosomes (and a stable version of FMR1 on the other X chromosome) make FMRP. Females who have the full FMR1 mutation on one of their X chromosomes (and a stable version of FMR1 on the other X chromosome) produce a reduced amount of FMRP.
There was a significantly higher prevalence of 'mosaic' cases among males with a full mutation (12%) than among females with a full mutation (6%); the mosaic males had a larger expansion than did the mosaic females. 'Mosaics' are individuals carrying the full mutation who also have some premutations in some of their cells. Among 164 independent couples, 3 unrelated husbands carried a premutation, suggesting that the prevalence of fragile X premutations in the general population is approximately 0.9% of the X chromosomes. The data validated the use of direct DNA testing for fragile X diagnosis and carrier identification.
FMR1 gene is subject to X inactivation by studying inactive X chromosomes in somatic cell hybrids that contained an active or inactive human X chromosome and in a female patient with a large deletion surrounding the FMR1 gene. The findings were consistent with the results of previous studies of DNA methylation of FMR1 and supported the involvement of X inactivation in the variable phenotype of females with full mutations of the FMR1 gene.
A Multicenter Study on Genotype-Phenotype Correlations in the Fragile X Syndrome, Using Direct Diagnosis with Probe StB12.3: The First 2,253 Cases
The major characteristics observed in individuals with fragile X syndrome are related to the functioning of the brain. In addition, males with fragile X syndrome often have macroorchidism, enlarged testicles. Thus, it is not surprising that in individuals who do not have fragile X syndrome, the brain and testicles are places where the protein is actively synthesized. In other words, humans typically make FMRP in the testicles and the brain; if they can't, problems occur and we call those problems fragile X syndrome.
There are also some other areas of the body that normally synthesize FMRP, such as the liver, lung, kidney spinal cord, and gastrointestinal tract. These are not areas of significant problems for persons with fragile X syndrome. There are two other proteins, FXR1 and FXR2, which share some structural and functional characteristics with FMRP. It may be that in these tissues, FXR1 and FXR2 are able to compensate for a lack of FMRP. Obviously, FXR1 and FXR2 are not able to compensate for an absence of FMRP in the brains and testicles.
Cellular function
FMRP has a cytoplasmatic localization.
This protein is normally made in many tissues, especially in the brain and testes. It may play a role in the development of synaptic connections between nerve cells in the brain, where cell-to-cell communication occurs. The connections between nerve cells can change and adapt over time in response to experience (a characteristic called synaptic plasticity). FMRP may help regulate synaptic plasticity, which is important for learning and memory.
ref
In Drosophila, Ishizuka found that FMR1 is a component of a large protein complex known as the RNA-induced silencing complex (RISC), which is a sequence-specific nuclease complex that mediates RNA interference (RNAi). FMR1 was found to associate with argonaute-2 and dicer 2 proteins normally present in the RISC. The findings suggested that defects in an RNAi-related machinery may underlie human diseas.
A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins
Probably the toxic role of FMRP is given from the mRNA.
The premutated mRNA has more affinity to the wild type mRNA to some citosolic protein and the bound between mRNA and protein cause the depletion from the cytosolic pool of this proteins that is normally used from the cell in order to carry out its physiological functions. At the same time pre-mutated mRNA of FMR1 draw the proteasoma’s protein and other cellular stress protein as HSP to degradated this toxic mRNA but the premutation give more stability to this RNA and is not easy to destroy it .The increase of CGG triplet’s number is associated with high level of mRNA (7-8 more than wild type) and more stability of this. At the end, this big complex (mRNA and protein) carries the cellular death.
