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)

The absence of the fragile X mental retardation protein (FMRP), encoded by the FMR1 gene, is responsible for pathologic manifestations in the Fragile X Syndrome, the most frequent cause of inherited mental retardation. FMRP is an RNA-binding protein associated with polysomes as part of a messenger ribonucleoprotein (mRNP) complex. Although its function is poorly understood, various observations suggest a role in local protein translation at neuronal dendrites and in dendritic spine maturation. We present here the identification of CYFIP1/2 (Cytoplasmic FMRP Interacting Proteins) as FMRP interactors. CYFIP1/2 share 88% amino acid sequence identity and represent the two members in humans of a highly conserved protein family. Remarkably, whereas CYFIP2 also interacts with the FMRP-related proteins FXR1P/2P, CYFIP1 interacts exclusively with FMRP. FMRP--CYFIP interaction involves the domain of FMRP also mediating homo- and heteromerization, thus suggesting a competition between interaction among the FXR proteins and interaction with CYFIP. CYFIP1/2 are proteins of unknown function, but CYFIP1 has recently been shown to interact with the small GTPase Rac1, which is implicated in development and maintenance of neuronal structures. Consistent with FMRP and Rac1 localization in dendritic fine structures, CYFIP1/2 are present in synaptosomal extracts.
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PMID:A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. 1143 99

Neuronal plasticity requires actin cytoskeleton remodeling and local protein translation in response to extracellular signals. Rho GTPase pathways control actin reorganization, while the fragile X mental retardation protein (FMRP) regulates the synthesis of specific proteins. Mutations affecting either pathway produce neuronal connectivity defects in model organisms and mental retardation in humans. We show that CYFIP, the fly ortholog of vertebrate FMRP interactors CYFIP1 and CYFIP2, is specifically expressed in the nervous system. CYFIP mutations affect axons and synapses, much like mutations in dFMR1 (the Drosophila FMR1 ortholog) and in Rho GTPase dRac1. CYFIP interacts biochemically and genetically with dFMR1 and dRac1. Finally, CYFIP acts as a dRac1 effector that antagonizes FMR1 function, providing a bridge between signal-dependent cytoskeleton remodeling and translation.
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PMID:CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein. 1281 67

In the zebrafish retinotectal system, retinal ganglion cells (RGCs) project topographically along anterior-posterior (A-P) and dorsal-ventral (D-V) axes to innervate their primary target, the optic tectum. In the nevermind (nev) mutant, D-V positional information is not maintained by dorsonasal retinal axons as they project through the optic tract to the tectum. Here we present a detailed phenotypic analysis of the retinotectal projection in nev and show that dorsonasal axons do eventually find their correct location on the tectum, albeit after taking a circuitous path. Interestingly, nev seems to be specifically required for retinal axons but not for several non-retinal axon tracts. In addition, we find that nev is required both cell autonomously and cell nonautonomously for proper lamination of the retina. We show that nev encodes Cyfip2 (Cytoplasmic FMRP interacting protein 2) and is thus the first known mutation in a vertebrate Cyfip family member. Finally, we show that CYFIP2 acts cell autonomously in the D-V sorting of dorsonasal RGC axons in the optic tract. CYFIP2 is a highly conserved protein that lacks known domains or structural motifs but has been shown to interact with Rac and the fragile-X mental retardation protein, suggesting intriguing links to cytoskeletal dynamics and RNA regulation.
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PMID:nev (cyfip2) is required for retinal lamination and axon guidance in the zebrafish retinotectal system. 2053 92

Intellectual disability (ID) and autism spectrum disorders (ASDs) have in common alterations in some brain circuits and brain abnormalities, such as synaptic transmission and dendritic spines morphology. Recent studies have indicated a differential expression for specific categories of genes as a cause for both types of disease, while an increasing number of genes is recognized to produce both disorders. An example is the Fragile X mental retardation gene 1 (FMR1), whose silencing causes the Fragile X syndrome, the most common form of ID and autism, also characterized by physical hallmarks. Fragile X mental retardation protein (FMRP), the protein encoded by FMR1, is an RNA-binding protein with an important role in translational control. Among the interactors of FMRP, CYFIP1/2 (cytoplasmic FMRP interacting protein) proteins are good candidates for ID and autism, on the bases of their genetic implication and functional properties, even if the precise functional significance of the CYFIP/FMRP interaction is not understood yet. CYFIP1 and CYFIP2 represent a link between Rac1, the WAVE (WAS protein family member) complex and FMRP, favoring the cross talk between actin polymerization and translational control.
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PMID:CYFIP family proteins between autism and intellectual disability: links with Fragile X syndrome. 2473 99