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Relevance to Autism

A rare CYFIP1 deletion was found in a patient with PDD-NOS and mild intellectual disability (Leblond et al., 2012).

Molecular Function

Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit is an adapter between EIF4E and FMR1. Promotes the translation repression activity of FMR1 in brain probably by mediating its association with EIF4E and mRNA. Regulates formation of membrane ruffles and lamellipodia. Plays a role in axon outgrowth. Binds to F-actin but not to RNA. Part of the WAVE complex that regulates actin filament reorganization via its interaction with the Arp2/3 complex. Actin remodeling activity is regulated by RAC1. Regulator of epithelial morphogenesis. May act as an invasion suppressor in cancers.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.
ASD
ID
Positive Association
A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus.
Inter-individual variation in surface area across
Positive Association
Common Regulatory Variants of CYFIP1 Contribute to Susceptibility for Autism Spectrum Disorder (ASD) and Classical Autism.
ASD
Positive Association
Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders.
ASD
Support
A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-...
Support
Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms
ASD, SCZ
Support
Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits
Support
Cytoplasmic FMRP interacting protein 1/2 (CYFIP1/2) expression analysis in autism.
Support
Comprehensive molecular testing in patients with high functioning autism spectrum disorder.
ASD
Support
Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.
ASD
Support
A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder.
ASD
Recent Recommendation
CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation.
Recent Recommendation
Autism and Schizophrenia-Associated CYFIP1 Regulates the Balance of Synaptic Excitation and Inhibition.
Recent Recommendation
Cyfip1 Regulates Presynaptic Activity during Development.
Recent Recommendation
Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks.
Recent Recommendation
Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.
Recent Recommendation
Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity.
Recent Recommendation
The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN320R001 
 copy_number_loss 
  
  
 Familial 
 Paternal 
 Simplex 
 GEN320R002 
 copy_number_gain 
  
  
 Familial 
 Paternal 
 Multi-generational 
 GEN320R003 
 missense_variant 
 c.2597G>C 
 p.Arg866Pro 
 Familial 
 Maternal 
 Multiplex 
 GEN320R004 
 missense_variant 
 c.287C>T 
 p.Ala96Val 
 Familial 
 Paternal 
 Multi-generational 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN320C001 
 missense_variant, splice_site_variant 
 rs7170637 
 c.1165G>A;c.2458G>A;c.2542G>A;c.2452G>A 
 p.Gly389Ser;p.Gly820Ser;p.Gly848Ser;p.Gly818Ser 
 Discovery cohort: 446 German ASD families (442 trios/4 duos); replication cohorts: Strict/European subsample from AGP (1466 trios) and French case/control sample (541 cases/366 controls) 
 Discovery and replication (meta-analysis) 
 GEN320C002 
 intron_variant 
 rs8028440 
 c.-125-4321C>T;c.-6-5059C>T;c.-831C>T;c.-33-5032C>T 
  
 2147 trios with probands diagnosed with ASD and a subset of 1266 trios with probands diagnosed with classical autism from the Autism Genome Project (AGP) 
 Discovery 
 GEN320C003 
 intron_variant 
 rs2289823 
 c.208-177C>T;c.292-177C>T 
  
 2147 trios with probands diagnosed with ASD and a subset of 1266 trios with probands diagnosed with classical autism from the Autism Genome Project (AGP) 
 Discovery 
 GEN320C004 
 intron_variant 
 rs7403800 
 c.569+1113A>G;c.653+1113A>G 
  
 2147 trios with probands diagnosed with ASD and a subset of 1266 trios with probands diagnosed with classical autism from the Autism Genome Project (AGP) 
 Discovery 
 GEN320C005 
 intron_variant 
 rs4778298 
 c.1360-629G>T;c.1444-629G>T 
  
 Discovery cohort: 100 unrelated adults (81 Caucasian). Validation cohort: 2621 healthy adults of Dutch descent (2383 Caucasian) 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
15
Duplication
 10
  construct
15
Duplication
 1
 
15
Duplication
 3
 
15
Duplication
 7
 
15
Duplication
 2
 
15
Duplication
 2
 
15
Deletion
 1
 
15
Deletion-Duplication
 98
 
15
Duplication
 66
  construct
15
Duplication
 5
 
15
Duplication
 14
 
15
Duplication
 3
 

Model Summary

The transgenic mice expressing Cyfip1 transgene, leading to increased production of the protein have increased mature dendritic spines and dendritic spine density.

References

Type
Title
Author, Year
Primary
Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.
Additional
Behavioral training rescues motor deficits in Cyfip1 haploinsufficiency mouse model of autism spectrum disorders.

M_CYFIP1_1_TG

Model Type: Genetic
Model Genotype: Transgenic
Mutation: Two transgenic strains (strain nos. 8 and 24) of second and third generation mice harboring a Cyfip1 spanning BAC clone generated by microinjection into fertilized C57BL/6 pronuclei, and showing a 1.5 and 2 fold increase in protein levels respectively (Fig 2E, F) in the adult hippocampus and a ~1.5 fold increase in cyfip1 transcript levels in strain number 8 in the E15 frontal cortex, P1 cerebellum, P11 hippocampus, and in adult frontal cortex and cerebellum (Fig S3).
Allele Type: Overexpression
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line:
Mutant ES Cell Line:
Model Source: UCLA transgenic core

M_CYFIP1_2_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Cyfip1 heterozygous knockouts were generated by the insertion of the L1L2_Bact_P targeting vector containing FRT, lacz, loxP, a second FRT and a second loxP site at position 55873080, and a third loxp site is intserted at position 55875575 downstream of the targeted exons on chromosome 7. Flp recombinase expression followed by Cre expression creates a floxed followed by a KO mouse. Cyfip1 tet mice are crossed with Tg(Thy1-EGFP)MJrs/J (JAX:00778851) to obtain reporter tagged Thy1-EGFP-Cyfip1-Het mice.
Allele Type: Knockout
Strain of Origin: C57BL/6N-A^tm1Brd
Genetic Background: C57Bl/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Not specified

M_CYFIP1_1_TG

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Dendritic architecture: spine density1
Increased
Description: Cyfip1 overexpression in mice causes an increase in spine density and neurite branches in layer ii-iii pyramidal neurons
Exp Paradigm: NA
 Golgi-cox staining
 2 months
Dendritic architecture: dendritic tree complexity1
Increased
Description: Cyfip1 overexpression in mice causes an increase in mature stubby spines (and a decrease in immature thin spines)
Exp Paradigm: NA
 Golgi-cox staining
 2 months
Brain cytoarchitecture1
Increased
Description: Cyfip1 overexpression in mice causes an increase in cell size in layer ii-iii pyramidal neurons of the frontal cortex
Exp Paradigm: NA
 Golgi-cox staining
 Unreported
Gene expression1
Decreased
Description: Cyfip1 overexpressing transgenice mice show a two fold reduced production of nrxn1
Exp Paradigm: NA
 Quantitative pcr (qrt-pcr)
 E15
Gene expression1
Decreased
Description: Cyfip1 overexpressing transgenice mice show a two fold reduced production of nlgn3
Exp Paradigm: NA
 Quantitative pcr (qrt-pcr)
 E15
Gene expression1
Decreased
Description: Cyfip1 overexpressing transgenice mice show a two fold reduced production of cntnap4
Exp Paradigm: NA
 Quantitative pcr (qrt-pcr)
 E15
Targeted expression1
Increased
Description: Cyfip1 overexpression in mice causes an increase
Exp Paradigm: NA
 NA
 2 months
Brain morphology1
 No change
 Histology
 Unreported
Brain size1
 No change
 Golgi-cox staining
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_CYFIP1_2_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Motor learning1
Decreased
Description: Mutants show decrease in latency to fall off the rotarod over multiple trials compared with control.
Exp Paradigm: NA
 Accelerating rotarod test
 Not reported
Dendritic architecture: spine density1
Decreased
Description: Mutants show a decrease in dendritic spine density in neurons from the motor cortex compared with controls.
Exp Paradigm: Motor cortex
 Immunofluorescence staining
 Adult
Dendritic architecture: spine turnover1
Increased
Description: Mutants show an increase in dendritic spine instability in the motor cortex compared with controls.
Exp Paradigm: Motor cortex
 Two-photon microscopy
 Adult
Social scent marking or recognition1
Decreased
Description: Mutants spent less time investigating social odor compared with controls.
Exp Paradigm: NA
 Olfactory discrimination test
 Not reported
Targeted expression1
Decreased
Description: Mutants show a decrease in cyfip1 protein expression in the motor and frontal cortices and in the hippocampus compared with controls.
Exp Paradigm: NA
 Western blot
 Not reported
Ultrasonic vocalization: interaction induced: opposite sex stimulus1
 No change
 Monitoring ultrasonic vocalizations
 Not reported
Targeted expression1
 No change
 Western blot
 Not reported
General locomotor activity1
 No change
 Accelerating rotarod test
 Not reported
General locomotor activity1
 No change
 Open field test
 Not reported
Dendritic architecture: spine density1
 No change
 Immunofluorescence staining
 Adult
Repetitive digging1
 No change
 Marble-burying test
 Not reported
 Not Reported: Circadian sleep/wake cycle, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Neurophysiology, Physiological parameters, Seizure, Sensory

 

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