Intellectual Disability and Behavioral Deficits Linked to CYFIP1 Missense Variants Disrupting Actin Polymerization
Open accessAbstract
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.
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Molecular and cellular analyses of skin fibroblasts from one proband revealed actin polymerization deficits, potentially due to impaired WAVE complex functionality and reduced CYFIP1 stability within the complex.
“Molecular and cellular analyses of skin fibroblasts from one proband revealed actin polymerization deficits, potentially due to impaired WAVE complex functionality and reduced CYFIP1 stability within the complex111.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [111]
These CYFIP1 mutations occur in protein domains responsible for maintaining interactions within the WAVE complex.
“These mutations occur in protein domains responsible for maintaining interactions within the WAVE complex.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [111]
Transgenic fly models with these CYFIP1 mutations presented abnormal neuronal morphology and F-actin loss, mirroring core behavioral symptoms such as social interaction and motor coordination deficits.
“Transgenic fly models with these mutations presented an abnormal neuronal morphology and F-actin loss, mirroring core behavioral symptoms such as social interaction and motor coordination deficits.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [111]
Compound heterozygous CYFIP1 variants p.Ile476Val and p.Pro742Leu were identified in two affected males from a family who exhibited developmental delay, intellectual disability, autism spectrum disorder, epilepsy, and absence of speech.
“Following the association of two common SNPs in CYFIP1 in SCZ patients110 (Table 2j), the compound heterozygous variants p.Ile476Val and p.Pro742Leu were identified via exome sequencing in two affected males from a family, who exhibited DD, ID, ASD, epilepsy, and an absence of speech (Table 2k).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [111]
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Self-citation
- Authors
- Mariano, V., Kanellopoulos, A. K., Ricci, C., Di Marino, D., Borrie, S. C., Dupraz, S., Bradke, F., Achsel, T., Legius, E., Odent, S., Billuart, P., Bienvenu, T., & Bagni, C.
- Affiliations
- University of Lausanne (CH)
- University of Rome Tor Vergata (IT)
- KU Leuven (BE)
- German Center for Neurodegenerative Diseases (DE)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Corresponding author
- Bagni, Claudia
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2024-01
- Volume
- 95
- Issue
- 2
- Pages
- 161-174
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W4386600589
- Cited by
- 14
- References
- 14
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 3 · 2023: 1
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biological Psychiatry (acceptedVersion)
- PubMed (publishedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion, cc-by-nc)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- IRIS (submittedVersion)
- Lirias (submittedVersion, other-oa)
- DZNE Pub (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030-182651, 310030_215706)
- Fondation Pierre Mercier
- Fondazione Telethon (GGP20137)
- National Center of Competence in Research Spin Qubit in Silicon (51NF40-158776)
- Ministero dell’Istruzione, dell’Università e della Ricerca
- European Commission (EXC2151–390873048)
- Novartis Stiftung für Medizinisch-Biologische Forschung
- Deutsche Forschungsgemeinschaft
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- International Foundation for Research in Paraplegia
- Université de Lausanne (2020-088)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- CYFIP1, missense mutations, intellectual disability, autism spectrum disorder, actin polymerization, WAVE regulatory complex, spastic tetraparesis, social interaction deficits, motor coordination deficits, neurodevelopmental disorders
- MeSH terms
- Autism Spectrum Disorder, Actins, Humans, Intellectual Disability, Adaptor Proteins, Signal Transducing, Fragile X Messenger Ribonucleoprotein 1, Polymerization
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