CYFIP family proteins between autism and intellectual disability: links with Fragile X syndrome

Abstract

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.

Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating

“…CYFIP1/2 is a component of the WAVE regulatory complex(45) and also associates with FMRP(46). Both WAVE and FMRP regulate dendritic spine morphology and synaptic plasticity(45, 47). CYFIP modulates protein interactions in the FMRP-ribosome complex(48) to regulate activity-dependent synaptic translation and plasticity.…”

“…Type I deletions comprise 40% of PWS deletions and can be associated with more severe neurobehavioral pathology, including an increase in compulsive behavior(70, 71). Based on our identification of Cyfip2 for BE ( Fig.3 ), the shared neurobiological function of CYFIP proteins(47) and the association of CYFIP1 with PWS, one hypothesis is that CYFIP1 polymorphisms also affect BE and hyperphagia.…”

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

“…These five autism-risk genes have been reported to be involved in the Rac1 signaling pathway. The cytoplasmic FMRP-interacting protein (CYFIP) directly links Rac1 and FMRP to modulate cytoskeleton remodeling (45); Tsc1 functionally regulates Rac1 activity (46,60); Ube3a promotes Rho-GEF Pbl degradation via ubiquitination to affect Rac1 activation (47); and upon synaptic activation Rho-GEF Kal-7 disassembles from the Nrx-1/Nlg4/DISC1 complex to modulate the Rac1 pathway (48). Several other autism-risk genes, such as Nlg1, Nrx-4, P-Rex1, and Shank-3, have also been reported to participate in the Rac1-signaling pathway (61)(62)(63)(64).…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…protein 48 , interacts with fragile X mental retardation protein (FMRP) [49][50][51][52][53] , which regulates the dendritic targeting of mRNAs 54 and controls mRNA decay and protein synthesis in the neuronal soma and at spines 50 . FMRP tethers specific mRNAs to CYFIP1, which then sequesters the capbinding protein eIF4E and mediates translational repression 55 ( Figure 1).…”