Intellectual Disability and Behavioral Deficits Linked to CYFIP1 Missense Variants Disrupting Actin Polymerization - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Biological Psychiatry Année : 2024

Intellectual Disability and Behavioral Deficits Linked to CYFIP1 Missense Variants Disrupting Actin Polymerization

Résumé

Background - 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. Methods - 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. Results - 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. Conclusions - 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.
Fichier principal
Vignette du fichier
Mariano et al-2023-Intellectual Disability and Behavioral Deficits Linked to CYFIP1 Missense.pdf (72.88 Mo) Télécharger le fichier
1-s2.0-S0006322323015639-mmc1.pdf (671.8 Ko) Télécharger le fichier
1-s2.0-S0006322323015639-mmc2.xlsx (18.12 Ko) Télécharger le fichier
1-s2.0-S0006322323015639-mmc3.mp4 (16.34 Mo) Télécharger le fichier
1-s2.0-S0006322323015639-mmc4.mp4 (6.28 Mo) Télécharger le fichier
ScienceDirect_files_22Nov2023_09-44-48.846.zip (23.14 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-04212584 , version 1 (22-11-2023)

Licence

Paternité - Pas d'utilisation commerciale

Identifiants

Citer

Vittoria Mariano, Alexandros K Kanellopoulos, C Ricci, Daniele Di Marino, Sarah C Borrie, et al.. Intellectual Disability and Behavioral Deficits Linked to CYFIP1 Missense Variants Disrupting Actin Polymerization. Biological Psychiatry, 2024, 95 (2), pp.161-174. ⟨10.1016/j.biopsych.2023.08.027⟩. ⟨hal-04212584⟩
33 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More