CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is overexpressed in Dup15q syndrome as well as autism spectrum disorder (ASD).
Overall, a synaptic pathway centered around FMR1, CYFIP1, and NLG3 is likely to contribute to the phenotypes associated with structural and physiological plasticity characteristic of ASD.
Altogether, these data provide new insight into the neuronal and behavioral phenotypes caused by Cyfip1 mutation and proof-of-concept for the development of a behavioral therapy to treat phenotypes associated with 15q11.2 syndromes and ASD.
We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders.
The current study provides further supports for contribution of CYFIP1/2 in the pathogenesis of ASD and potentiates it as a peripheral marker for ASD diagnosis.
Cytoplasmic FMR1-interacting protein 1 (CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions of CYFIP1 in patients with schizophrenia and intellectual disability.
The predicted impact on transcription through the ASD associated EIF4E variants rs4699369T and rs12498533G as well as the association of the EIF4E interaction partners FMRP and CYFIP1 with ASD point to an mRNA mediated pathomechanism for ASD.
These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk.