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@ARTICLE{Mariano:266342,
author = {Mariano, Vittoria and Kanellopoulos, Alexandros K. and
Ricci, Carlotta and Di Marino, Daniele and Borrie, Sarah C.
and Dupraz, Sebastian and Bradke, Frank and Achsel, Tilmann
and Legius, Eric and Odent, Sylvie and Billuart, Pierre and
Bienvenu, Thierry and Bagni, Claudia},
title = {{I}ntellectual {D}isability and {B}ehavioral {D}eficits
{L}inked to {CYFIP}1 {M}issense {V}ariants {D}isrupting
{A}ctin {P}olymerization},
journal = {Biological psychiatry},
volume = {95},
number = {2},
issn = {0006-3223},
address = {Amsterdam [u.a.]},
publisher = {Elsevier Science},
reportid = {DZNE-2023-01127},
pages = {161 - 174},
year = {2024},
abstract = {15q11.2 deletions and duplications have been linked to
autism spectrum disorder, schizophrenia, and intellectual
disability. Recent evidence suggests that dysfunctional
CYFIP1 (cytoplasmic FMR1 interacting protein 1) contributes
to the clinical phenotypes observed in individuals with
15q11.2 deletion/duplication syndrome. CYFIP1 plays crucial
roles in neuronal development and brain connectivity,
promoting actin polymerization and regulating local protein
synthesis. However, information about the impact of single
nucleotide variants in CYFIP1 on neurodevelopmental
disorders is limited.Here, we report a family with 2
probands exhibiting intellectual disability, autism spectrum
disorder, spastic tetraparesis, and brain morphology defects
and who carry biallelic missense point mutations in the
CYFIP1 gene. We used skin fibroblasts from one of the
probands, the parents, and typically developing individuals
to investigate the effect of the variants on the
functionality of CYFIP1. In addition, we generated
Drosophila knockin mutants to address the effect of the
variants in vivo and gain insight into the molecular
mechanism that underlies the clinical phenotype.Our study
revealed that the 2 missense variants are in protein domains
responsible for maintaining the interaction within the wave
regulatory complex. Molecular and cellular analyses in skin
fibroblasts from one proband showed deficits in actin
polymerization. The fly model for these mutations exhibited
abnormal brain morphology and F-actin loss and recapitulated
the core behavioral symptoms, such as deficits in social
interaction and motor coordination.Our findings suggest that
the 2 CYFIP1 variants contribute to the clinical phenotype
in the probands that reflects deficits in actin-mediated
brain development processes.},
keywords = {Humans / Intellectual Disability: genetics / Actins:
genetics / Actins: metabolism / Autism Spectrum Disorder:
genetics / Autism Spectrum Disorder: metabolism /
Polymerization / Adaptor Proteins, Signal Transducing:
genetics / Fragile X Mental Retardation Protein: metabolism
/ Actins (NLM Chemicals) / Actin remodeling (Other) / Autism
spectrum disorder (Other) / CYFIP1 (Other) / Drosophila
(Other) / Motor impairment (Other) / Social deficits (Other)
/ Adaptor Proteins, Signal Transducing (NLM Chemicals) /
CYFIP1 protein, human (NLM Chemicals) / FMR1 protein, human
(NLM Chemicals) / Fragile X Mental Retardation Protein (NLM
Chemicals)},
cin = {AG Bradke},
ddc = {610},
cid = {I:(DE-2719)1013002},
pnm = {351 - Brain Function (POF4-351)},
pid = {G:(DE-HGF)POF4-351},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37704042},
doi = {10.1016/j.biopsych.2023.08.027},
url = {https://pub.dzne.de/record/266342},
}