Fragile X mental retardation 1
PDB rendering based on 2bkd.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2BKD, 2FMR, 2LA5, 2QND
Identifiers
Symbols	FMR1; FMRP; FRAXA; POF; POF1
External IDs	OMIM: 309550 MGI: 95564 HomoloGene: 1531 GeneCards: FMR1 Gene
Gene Ontology Molecular function • RNA binding • RNA binding • mRNA binding • protein binding Cellular component • soluble fraction • nucleus • nucleoplasm • nucleolus • cytoplasm • mRNA cap binding complex • polysomal ribosome Biological process • transport • central nervous system development • negative regulation of translational initiation • mRNA transport Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2332	14265
Ensembl	ENSG00000102081	ENSMUSG00000000838
UniProt	Q06787	P35922
RefSeq (mRNA)	NM_001185075.1	NM_008031.2
RefSeq (protein)	NP_001172004.1	NP_032057.2
Location (UCSC)	Chr X: 146.99 – 147.03 Mb	Chr X: 65.93 – 65.97 Mb
PubMed search	[2]	[3]
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Location of FMR1 on the X chromosome.

FMR1 (fragile X mental retardation 1) is a human gene^[1] that codes for a protein called fragile X mental retardation protein, or FMRP.^[2] This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function. Mutations of this gene can lead to fragile X syndrome, mental retardation, premature ovarian failure, autism, Parkinson's disease, developmental delays and other cognitive deficits.^[3]

FMR1 gene expression[link]

The FMR1 gene is located on the 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.^[4]

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

Related conditions[link]

Fragile X syndrome[link]

Almost all cases of 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, which makes this region of the gene unstable. As a result, 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 mutations that delete part or all of the FMR1 gene, or change a base pair, leading to a change in one of the 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 about 55 to 200 times is described as a premutation expansion. Men, and probably some women, with this premutation do not have fragile X syndrome, but are at increased risk of developing a disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is characterized by progressive movement problems (ataxia), tremor, memory loss, loss of sensation in the lower extremities (peripheral neuropathy) and mental and behavioral changes. The disorder usually develops late in life.

Although most men and women 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 emotional problems such as anxiety or depression. About 20 % of women who carry a premutation expansion in the FMR1 gene experience premature ovarian failure (POF). POF is a loss of ovarian function in women younger than age 40, which can result in infertility. However, as fragile X is an X-linked recessive disorder, most females with premutation or even full mutation do not exhibit symptoms due to a second, normal X-chromosome.

Researchers have found that some children with a premutation expansion in the FMR1 gene have learning disabilities, mental retardation, or disorders in the autism spectrum, characterized by deficits in communication and social interaction.

Premature ovarian aging[link]

In recent years scientists have discovered that 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 fragile X syndrome are associated with an increased risk for premature ovarian aging, also called occult primary ovarian insufficiency, a condition in which women prematurely deplete their ovarian function^[5][6][7][8]

Polycystic ovarian syndrome[link]

A very specific sub-genoype of FMR1 has been found to be 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. This leads to premature depletion of ovarian reserve and these women often suffer from premature ovarian aging when they are older.^[9]

FMRP function[link]

Synaptic plasticity[link]

As mentioned, 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 mRNA, dendritic mRNA localization, and synaptic protein synthesis.^[10] 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 synaptic plasticity.^[11] Synaptic plasticity requires the production of new proteins in response to activation of synaptic receptors (biochemistry). 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 second messenger system.^[12] A role for mGluR in synaptic plasticity is further evidenced by the observation of dendritic spine elongation following mGluR stimulation.^[13] Furthermore, mGluR activation results in the synthesis of FMRP near 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(biology). This further advocates a role for FMRP in synaptic protein synthesis and the growth of synaptic connections.^[14] Interestingly, the loss of FMRP results in an abnormal dendritic spine phenotype. Specifically, deletion of the FMR1 gene in a sample of mice resulted in a reduction in spine synapse number.^[15]

Role in translation[link]

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 polyribosomes.^[14][16] The RNA-binding abilities of FMRP are dependent upon its 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.^[17]

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.^[18] 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.^[19]

FMRP translation repression acts by inhibiting the initiation of translation. FMRP directly binds CYFIP1, which in turn binds the translation initiation factor eIF4E. The FMRP-CYFIP1 complex prohibits eIF4E-dependent initiation, thereby acting to repress translation.^[20] 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.^[20][21] 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 Arc/Arg3.1 and MAP1B, and the CaMKII kinase.^[22] In addition, FMRP binds 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 MAP1B mRNA and ribosomal RNA in dendrites, suggesting this complex as a whole may need to be transported to dendrites for local protein synthesis. In addition, microtubules were found to be a necessary component for the mGluR-dependent translocation of FMRP into dendrites.^[10] FMRP may play an additional role in local protein synthesis by aiding in the association of mRNA cargo and microtubules.^[23] Thus, FMRP is able to regulate transport efficacy, as well as repression of translation during transport. Finally, FMRP synthesis, ubiquitination, and proteolysis occur rapidly in response to mGluR signaling, suggesting an extremely dynamic role of the translational regulator.^[19]

Interactions[link]

FMR1 has been shown to interact with FXR2,^[24][25][26] CYFIP1,^[27] CYFIP2,^[27][28] NUFIP1,^[28][29] FXR1,^[24][26] and NUFIP2.^[28]

References[link]

Further reading[link]

External links[link]

• GeneCard
• fragilex at NIH/UW GeneTests

v t e PDB gallery 2bkd: STRUCTURE OF THE N-TERMINAL DOMAIN OF FRAGILE X MENTAL RETARDATION PROTEIN   2fmr: KH1 FROM THE FRAGILE X PROTEIN FMR1, NMR, 18 STRUCTURES

This biographical article needs additional citations for verification. Please help by adding reliable sources. Contentious material about living persons that is unsourced or poorly sourced must be removed immediately, especially if potentially libelous or harmful. (September 2009)

Steve Warren, (born January 22, 1978) is a former defensive tackle who played for the Green Bay Packers of the National Football League (2000–02).^[1]

Collegiate career[link]

Warren played college football for the University of Nebraska.

Professional career[link]

Warren was drafted in the 3rd round of the 2000 NFL Draft by the Green Bay Packers. He played a backup role behind Cletidus Hunt after starter Santana Dotson went out for the season with an injury. Warren was injured in a November contest against the Chicago Bears and missed the remainder of the season.

After nursing his quadricep injury all offseason, he was still not ready to go at the start of the season. He was placed on the Physically Unable to Perform (PUP) list on August 28, 2001. After his six weeks on the PUP list, he was quoted as saying he was "Ready to go", but the Packers decided he was not ready to go and would be out the remainder of the season.

In 2002, Warren practiced during mini-camp and played most of 2002 season. He was inactive for a few contests but filled in for injured DL Billy Lyon in the Packers Wild Card loss to the Michael Vick lead Atlanta Falcons.

In 2003, Warren was tendered a minimum contract. In July of '03, Warren failed his physical for undisclosed reasons and was placed on the PUP list in late July with a back injury. On August 6, Warren was taken off the PUP list but he was released before the start of the regular season on August 26, 2003. The Kansas City Chiefs showed interest in signing Warren after his release from the Packers but they did not sign him.

References[link]