# FMR1

## Overview
The FMR1 gene is a critical component of human genetics, encoding the fragile X mental retardation protein (FMRP), an RNA-binding protein that plays a pivotal role in the regulation of mRNA translation within neurons. FMRP is characterized by its RNA-binding domains, including two K-homologous (KH) domains and an arginine-glycine-rich (RGG) box, which are essential for its function in synaptic plasticity and neuronal communication (Khandjian1999Biology; Siomi1993The). As a translational repressor, FMRP modulates the synthesis of proteins at synapses, influencing synaptic maturation and activity (Oostra2003A; Bardoni1999A). The absence or dysfunction of FMRP, due to mutations in the FMR1 gene, is the primary cause of fragile X syndrome, the most common inherited form of intellectual disability (Pugin2017Clinical; Mila2017Fragile). Additionally, premutation carriers of the FMR1 gene are at risk for conditions such as Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI), highlighting the gene's broad clinical significance (Hagerman2013Advances; Mila2017Fragile).

## Structure
The FMR1 gene encodes the fragile X mental retardation protein (FMRP), which is characterized by several RNA-binding domains. The primary structure of FMRP includes two K-homologous (KH) domains and an arginine-glycine-rich (RGG) box, both of which are crucial for its RNA-binding activity (Khandjian1999Biology; Siomi1993The). The KH domains are highly conserved and are involved in specific RNA recognition, while the RGG box enhances RNA-binding affinity (Khandjian1999Biology; ADINOLFI1999Dissecting).

The secondary structure of FMRP includes regions that form beta-sheets and alpha-helices, contributing to its ability to bind RNA (Siomi1996Specific). The tertiary structure involves the folding of these elements into a three-dimensional shape, which is essential for its function. The KH1 domain is capable of independent folding, while the KH2 domain requires stabilization by adjacent regions (ADINOLFI1999Dissecting).

FMRP can form homodimers, indicating a quaternary structure (Khandjian1999Biology). Post-translational modifications, such as phosphorylation, are also present, affecting the protein's function and interactions (Verhelj1995Characterization). FMRP exists in multiple splice variant isoforms, which may differ in their RNA-binding capabilities and tissue distribution (Verhelj1995Characterization).

## Function
The FMR1 gene encodes the fragile X mental retardation protein (FMRP), which is a crucial RNA-binding protein involved in the regulation of mRNA translation in neurons. FMRP contains two KH domains and an RGG box, which facilitate its RNA-binding capabilities (Oostra2003A; Bardoni1999A). In healthy human cells, FMRP is primarily found in the cytoplasm, where it associates with polysomes and is involved in the local synthesis of proteins at synapses, a process essential for synaptic plasticity and function (Oostra2003A; Mila2017Fragile).

FMRP acts as a translational repressor, modulating the translation of specific mRNAs, including those with G-quartet structures, which are important for synaptic maturation and activity (Oostra2003A; Mila2017Fragile). It is involved in the transport of mRNA between the nucleus and cytoplasm, facilitated by its nuclear localization and export signals (Oostra2003A). FMRP's role in synaptic function is further highlighted by its regulation of ionotropic glutamate receptor internalization, which is crucial for long-term synaptic plasticity (Oostra2003A).

The absence of FMRP, as seen in fragile X syndrome, leads to dysregulation of synaptic receptor internalization and excessive long-term depression, resulting in synaptic dysfunction (Oostra2003A; Mila2017Fragile).

## Clinical Significance
Mutations and alterations in the FMR1 gene are associated with several disorders, most notably Fragile X Syndrome (FXS), which is the most common inherited cause of intellectual disability. FXS is primarily caused by the expansion of CGG trinucleotide repeats in the FMR1 gene, leading to hypermethylation and silencing of the gene, resulting in the absence of the fragile X mental retardation protein (FMRP) (Pugin2017Clinical; Mila2017Fragile). This absence affects synaptic plasticity and cognitive function, manifesting in intellectual disabilities, autism spectrum disorders, and physical features such as large ears and flat feet (Pugin2017Clinical; Mila2017Fragile).

Premutation carriers, with 55-200 CGG repeats, do not exhibit the full symptoms of FXS but are at risk for Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI). These conditions are linked to increased FMR1 mRNA levels, leading to RNA toxicity and neurodegenerative symptoms such as tremor and ataxia (Hagerman2013Advances; Mila2017Fragile). Premutation carriers may also experience psychiatric disorders, reproductive challenges, and other health issues (Mila2017Fragile). Rare point mutations in the FMR1 gene can also cause FXS-like phenotypes, contributing to a range of clinical features including intellectual disability and seizures (Sitzmann2017Rare).

## Interactions
The FMR1 gene encodes the Fragile X Mental Retardation Protein (FMRP), which is involved in various protein and nucleic acid interactions. FMRP interacts with homologous proteins FXR1 and FXR2, forming complexes that are not easily dissociated by high salt concentrations, indicating strong interactions. These interactions suggest that FXR1 and FXR2 may regulate FMRP's function, potentially through oligomerization or by sequestering FMRP into inert complexes (Zhang1995The).

FMRP also interacts with ribosomal subunits, specifically associating with 60S ribosomal subunits, as confirmed by immunoprecipitation experiments. This interaction is resistant to treatments with EDTA or RNase, suggesting a robust association (Siomi1996Specific).

In the nucleus, FMRP interacts with several proteins, including FXR1P, Ddx41, Poldip3, and Hnrnpa3, which are involved in mRNA biogenesis processes such as transcription, splicing, and export. These interactions highlight FMRP's role in nuclear functions beyond its known cytoplasmic activities (Kieffer2022Combining).

FMRP also forms complexes with nucleolin, existing in both nucleolar and cytosolic forms. The cytosolic complex is part of a high molecular weight assembly, while the nucleolar complex is smaller, suggesting distinct functional roles in different cellular compartments (Taha2014Subcellular).


## References


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