Prof. Dr. Frank Bradke
German Center for Neurodegenerative Diseases (DZNE)firstname.lastname@example.org View member: Prof. Dr. Frank Bradke
BACKGROUND: 15q11.2 Deletions and duplications have been linked to autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID). Recent evidence suggests that dysfunctional Cytoplasmic FMR1 Interacting Protein 1 (CYFIP1) 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, the impact of single nucleotide variants in CYFIP1 to neurodevelopmental disorders is limited.
METHODS: Here, we report a family with two probands exhibiting ID, ASD, spastic tetraparesis, and brain morphology defects carrying biallelic missense point mutations in the CYFIP1 gene. We used skin fibroblasts from one of the proband, parents, and typically developing individuals to investigate the effect of the variants on the functionality of CYFIP1. In addition, we generated Drosophila knock-in mutants to address the effect of the variants in vivo and gain insight into the molecular mechanism underlying the clinical phenotype.
RESULTS: Our study revealed that the two missense variants are in protein domains responsible for maintaining the interaction within the wave regulatory complex (WRC). 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 two CYFIP1 variants contribute to the clinical phenotype observed in the proband that reflects deficits in actin-mediated brain development processes.
Copyright © 2023. Published by Elsevier Inc.