Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fragile X syndrome, the most common form of hereditary mental retardation, usually results from lack of expression of the FMR1 gene. The FMR1 protein is a cytoplasmic RNA-binding protein. The RNA-binding activity of FMR1 is an essential feature of FMR1, as fragile X syndrome can also result from the expression of mutant FMR1 protein that is impaired in RNA binding. Recently, we described two novel cytoplasmic proteins, FXR1 and FXR2, which are both very similar in amino acid sequence to FMR1 and which also interact strongly with FMR1 and with each other. To understand the function of FMR1 and the FXR proteins, we carried out cell fractionation and sedimentation experiments with monoclonal antibodies to these proteins to characterize the complexes they form. Here, we report that the FMR1 and FXR proteins are associated with ribosomes, predominantly with 60S large ribosomal subunits. The FXR proteins are associated with 60S ribosomal subunits even in cells that lack FMR1 and that are derived from a fragile X syndrome patient, indicating that FMR1 is not required for this association. We delineated the regions of FMR1 that mediate its binding to 60S ribosomal subunits and the interactions among the FMR1-FXR family members. Both regions contain sequences predicted to have a high propensity to form coiled coil interactions, and the sequences are highly evolutionarily conserved in this protein family. The association of the FMR1, FXR1, and FXR2 proteins with ribosomes suggests they have functions in translation or mRNA stability.
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PMID:Specific sequences in the fragile X syndrome protein FMR1 and the FXR proteins mediate their binding to 60S ribosomal subunits and the interactions among them. 866

The fragile X syndrome is caused by the amplification of a polymorphic CGG repeat in the 5' untranslated region of the FMR1 gene and is the most common form of inherited mental retardation. When the repeat is amplified beyond 200 repeat units, the repeat and the FMR1 promoter region are methylated. As a result of this methylation the gene is silenced and no FMR1 gene product (FMRP) is translated. The lack of expression of FMRP in the fragile X syndrome causes the fragile X phenotype. A mouse model for the fragile X syndrome (knockout for FMRP) has been generated to study the pathological mechanisms leading to the symptoms seen in fragile X patients. FMRP is widely expressed in different tissues and localized predominantly in the cytoplasm associated with the 60S ribosomal subunit. The protein has RNA binding properties and possibly shuttles between cytoplasm and nucleus. The target signals necessary for this intracellular transport, like a nuclear location signal and a nuclear export signal, are present in FMRP. FMRP is also able to bind to other proteins by using specific sequence domains present in the protein. The coiled-coil structures formed by these domains are known to be involved in protein-protein interaction. In this review we postulate that FMRP is involved in the transport of RNA and/or proteins from the nucleus to the cytoplasm.
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PMID:The fragile X syndrome. 921 Nov 86

Lack of expression of the fragile X mental retardation protein (FMRP) results in mental retardation and macroorchidism, seen as the major pathological symptoms in fragile X patients. FMRP is a cytoplasmic RNA-binding protein which cosediments with the 60S ribosomal subunit. Recently, two proteins homologous to FMRP were discovered: FXR1 and FXR2. These novel proteins interact with FMRP and with each other and they are also associated with the 60S ribosomal subunit. Here, we studied the expression pattern of the three proteins in brain and testis by immunohistochemistry. In adult brain, FMR1, FXR1 and FXR2 proteins are coexpressed in the cytoplasm of specific differentiated neurons only. However, we observed a different expression pattern in fetal brain as well as in adult and fetal testis, suggesting independent functions for the three proteins in those tissues during embryonic development and adult life.
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PMID:Differential expression of FMR1, FXR1 and FXR2 proteins in human brain and testis. 925 78

Fragile X syndrome is the most common inherited form of mental retardation. It is caused by loss of FMR1 gene activity due to either lack of expression or expression of a mutant form of the protein. In mammals, FMR1 is a member of a small protein family that consists of FMR1, FXR1, and FXR2. All three members bind RNA and contain sequence motifs that are commonly found in RNA-binding proteins, including two KH domains and an RGG box. The FMR1/FXR proteins also contain a 60S ribosomal subunit interaction domain and a protein-protein interaction domain which mediates homomer and heteromer formation with each family member. Nevertheless, the specific molecular functions of FMR1/FXR proteins are unknown. Here we report the cloning and characterization of a Drosophila melanogaster homolog of the mammalian FMR1/FXR gene family. This first invertebrate homolog, termed dfmr1, has a high degree of amino acid sequence identity/similarity with the defined functional domains of the FMR1/FXR proteins. The dfmr1 product binds RNA and is similar in subcellular localization and embryonic expression pattern to the mammalian FMR1/FXR proteins. Overexpression of dfmr1 driven by the UAS-GAL4 system leads to apoptotic cell loss in all adult Drosophila tissues examined. This phenotype is dependent on the activity of the KH domains. The ability to induce a dominant phenotype by overexpressing dfmr1 opens the possibility of using genetic approaches in Drosophila to identify the pathways in which the FMR1/FXR proteins function.
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PMID:Characterization of dFMR1, a Drosophila melanogaster homolog of the fragile X mental retardation protein. 1104 49

Lack of fragile X mental retardation protein (FMRP) causes the fragile X syndrome, a common form of inherited mental retardation. The syndrome usually results from the expansion of a CGG repeat in the FMR1 gene with consequent transcriptional silencing of FMR1. However, one missense mutation (Ile304Asn) was reported in the second KH domain of the protein involved in RNA binding. The protein containing this mutation showed an impaired function, leading to an extremely severe phenotype. In the present report, we have studied the role of FMRP I304N in living PC12 cells to better understand the (dys) function of this mutant FMRP. We have generated an FMR1 I304N-EGFP stably transfected PC12 cell line with an inducible expression system (Tet-On) for regulated expression of the FMRP I304N-EGFP fusion protein. After Dox-induction, FMRP I304N-EGFP was localized in the neurites of PC12 cells; however, no granules were formed as has been recently demonstrated for the normal FMRP. Time-lapse microscopy in combination with bleaching technology illustrated that although FMRP I304N-EGFP does not form visible granules, the transport into the neurites is microtubule dependent. Immunoprecipitation with antibodies against GFP demonstrates that FMRP I304N-EGFP coprecipitate with both the 60S ribosomal protein P0 and FXR1P, suggesting that the mutant FMRP is still able to form complexes, however, with different characteristics compared to normal FMRP.
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PMID:Transport kinetics of FMRP containing the I304N mutation of severe fragile X syndrome in neurites of living rat PC12 cells. 1538 Apr 84