Journal Article

DZNE-2023-01127

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Intellectual Disability and Behavioral Deficits Linked to CYFIP1 Missense Variants Disrupting Actin Polymerization

Mariano, V. ; Kanellopoulos, A. K. ; Ricci, C. ; Di Marino, D. ; Borrie, S. C. ; Dupraz, S.DZNE* ; Bradke, F.DZNE* ; Achsel, T. ; Legius, E. ; Odent, S. ; Billuart, P. ; Bienvenu, T. ; Bagni, C.

2024
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.biopsych.2023.08.027

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.

Keyword(s): Humans (MeSH) ; Intellectual Disability: genetics (MeSH) ; Actins: genetics (MeSH) ; Actins: metabolism (MeSH) ; Autism Spectrum Disorder: genetics (MeSH) ; Autism Spectrum Disorder: metabolism (MeSH) ; Polymerization (MeSH) ; Adaptor Proteins, Signal Transducing: genetics (MeSH) ; Fragile X Mental Retardation Protein: metabolism (MeSH) ; Actins ; Actin remodeling ; Autism spectrum disorder ; CYFIP1 ; Drosophila ; Motor impairment ; Social deficits ; Adaptor Proteins, Signal Transducing ; CYFIP1 protein, human ; FMR1 protein, human ; Fragile X Mental Retardation Protein

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Contributing Institute(s):

1. Axon Growth and Regeneration (AG Bradke)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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