FMR1



FMR1 (fragile X mental retardation 1) is a is_associated_with::human is_associated_with::gene that codes for a is_associated_with::protein called  f ragile X m ental r etardation p rotein, or FMRP. This protein, most commonly found in the brain, is essential for normal is_associated_with::cognitive development and female reproductive function. Mutations of this gene can lead to is_associated_with::fragile X syndrome, mental retardation, is_associated_with::premature ovarian failure, is_associated_with::autism, is_associated_with::Parkinson's disease, developmental delays and other cognitive deficits.

FMR1 gene expression
The FMR1 gene is located on the is_associated_with::X chromosome and contains a DNA segment called CGG trinucleotide. In most people, the CGG segment is repeated in the gene approximately 5-44 times. Increased expression of the CGG segment on the FMR1 gene is associated with impaired cognitive and reproductive function. If a person has 45-54 repeats this is considered the “gray zone” or borderline risk, 55-200 repeats is called premutation and more than 200 repeats is considered a full mutation of the FMR1 gene according to the American College of Medical Genetics and Genomics. The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using is_associated_with::SMRT sequencing.

The FMR1 gene can be found on the long (q) arm of the is_associated_with::X chromosome at position 27.3, from is_associated_with::base pair 146,699,054 to base pair 146,738,156.

Fragile X syndrome
Almost all cases of is_associated_with::fragile X syndrome are caused by expansion of the CGG trinucleotide repeat in the FMR1 gene. In these cases, CGG is abnormally repeated from 200 to more than 1,000 times. As a result, this part of the FMR1 gene is methylated, which silences the gene (it is turned off and does not make any protein). Without adequate FMRP, severe learning deficits or mental retardation can develop, along with physical abnormalities seen in fragile X syndrome.

Fewer than 1% of all cases of fragile X syndrome are caused by is_associated_with::mutations that delete part or all of the FMR1 gene, or change a base pair, leading to a change in one of the is_associated_with::amino acids in the gene. These mutations disrupt the 3-dimensional shape of FMRP or prevent the protein from being synthesized, leading to the signs and symptoms of fragile X syndrome.

A CGG sequence in the FMR1 gene that is repeated between 55 and 200 times is described as a premutation. Although most individuals with the premutation are intellectually normal, some of these individuals have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience mental health problems such as anxiety or depression.

Fragile X-associated tremor/ataxia syndrome
Premutations are associated with an increased risk of is_associated_with::fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is characterized by is_associated_with::ataxia (loss of coordination), is_associated_with::tremor, is_associated_with::memory loss, loss of sensation in the lower extremities (is_associated_with::peripheral neuropathy) and mental and behavioral changes. The disorder usually develops late in life.

Premature ovarian aging
The FMR1 gene plays a very important role in ovarian function, independent from cognitive/neurological effects. Minor expansions of CGG repeats that do not cause is_associated_with::fragile X syndrome are associated with an increased risk for is_associated_with::premature ovarian aging, also called occult primary ovarian insufficiency, a condition in which women prematurely deplete their ovarian function.

Polycystic ovarian syndrome
A very specific sub-genotype of FMR1 has been found to be associated with is_associated_with::polycystic ovarian syndrome (PCOS). The gene expression, called heterozygous-normal/low may cause PCOS-like excessive follicle-activity and hyperactive ovarian function when women are younger.

Synaptic plasticity
Fragile X syndrome is caused by the loss of production of fragile X mental retardation protein (FMRP) in response to FMR1 gene silencing. FMRP has a diverse array of functions throughout different areas of the neuron; however these functions have not been fully characterized. FMRP has been suggested to play roles in nucleocytoplasmic shuttling of is_associated_with::mRNA, dendritic mRNA localization, and synaptic is_associated_with::protein synthesis. Studies of Fragile X syndrome have significantly aided in the understanding of the functionality of FMRP through the observed effects of FMRP loss on neurons. A mouse model of fragile X mental retardation implicated the involvement of FMRP in is_associated_with::synaptic plasticity. Synaptic plasticity requires the production of new proteins in response to activation of synaptic receptors. It is the production of proteins in response to stimulation which is hypothesized to allow for the permanent physical changes and altered synaptic connections that are linked with the processes of learning and memory.

Group 1 metabotropic glutamate receptor (mGluR) signaling has been implicated in playing an important role in FMRP-dependent synaptic plasticity. Post-synaptic mGluR stimulation results in the up-regulation of protein synthesis through a is_associated_with::second messenger system. A role for mGluR in synaptic plasticity is further evidenced by the observation of is_associated_with::dendritic spine elongation following mGluR stimulation. Furthermore, mGluR activation results in the synthesis of FMRP near is_associated_with::synapses. The produced FMRP associates with polyribosomal complexes after mGluR stimulation, proposing the involvement of fragile X mental retardation protein in the process of translation. This further advocates a role for FMRP in synaptic protein synthesis and the growth of synaptic connections. Interestingly, the loss of FMRP results in an abnormal is_associated_with::dendritic spine phenotype. Specifically, deletion of the FMR1 gene in a sample of mice resulted in an increase in spine synapse number.

Role in translation
The proposed mechanism of FMRP’s effect upon synaptic plasticity is through its role as a negative regulator of translation. FMRP is an RNA-binding protein which associates with is_associated_with::polyribosomes. The RNA-binding abilities of FMRP are dependent upon its is_associated_with::KH domains and RGG boxes. The KH domain is a conserved motif which characterizes many RNA-binding proteins. Mutagenesis of this domain resulted in impaired FMRP binding to RNA.

FMRP has been shown to inhibit translation of mRNA. Mutation of the FMRP protein resulted in the inability to repress translation as opposed to the wild-type counterpart which was able to do so. As previously mentioned, mGluR stimulation is associated with increased FMRP protein levels. In addition, mGluR stimulation results in increased levels of FMRP target mRNAs. A study found basal levels of proteins encoded by these target mRNAs to be significantly elevated and improperly regulated in FMRP deficient mice.

FMRP translation repression acts by inhibiting the initiation of translation. FMRP directly binds is_associated_with::CYFIP1, which in turn binds the translation initiation factor is_associated_with::eIF4E. The FMRP-CYFIP1 complex prohibits eIF4E-dependent initiation, thereby acting to repress translation. When applied to the observed phenotype in fragile X Syndrome, the excess protein levels and reduction of translational control can be explained by the loss of translational repression by FMRP in fragile X syndrome. FMRP acts to control translation of a large group of target mRNAs; however the extent of FMRPs translational control is unknown. The protein has been shown to repress the translation of target mRNAs at synapses, including those encoding the cytoskeletal proteins is_associated_with::Arc/Arg3.1 and is_associated_with::MAP1B, and the CaM kinase II. In addition, FMRP binds is_associated_with::PSD-95 and GluR1/2 mRNAs. Importantly, these FMRP-binding mRNAs play significant roles in neuronal plasticity.

FMRP translational control has been shown to be regulated by mGluR signaling. mGluR stimulation may result in the transportation of mRNA complexes to synapses for local protein synthesis. FMRP granules have been shown to localize with is_associated_with::MAP1B mRNA and is_associated_with::ribosomal RNA in dendrites, suggesting this complex as a whole may need to be transported to dendrites for local protein synthesis. In addition, is_associated_with::microtubules were found to be a necessary component for the mGluR-dependent translocation of FMRP into dendrites. FMRP may play an additional role in local protein synthesis by aiding in the association of mRNA cargo and microtubules. Thus, FMRP is able to regulate transport efficacy, as well as repression of translation during transport. Finally, FMRP synthesis, is_associated_with::ubiquitination, and is_associated_with::proteolysis occur rapidly in response to mGluR signaling, suggesting an extremely dynamic role of the translational regulator.

Interactions
FMR1 has been shown to interact with:
 * is_associated_with::CYFIP1, ''
 * is_associated_with::CYFIP2, ''
 * is_associated_with::FXR1, and ''
 * is_associated_with::FXR2,  ''
 * is_associated_with::NUFIP1, '' and
 * is_associated_with::NUFIP2.