CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2
Abstract
Here, we report the generation and comprehensive characterization of a knockin mouse model for the hotspot p.Arg87Cys variant of the cytoplasmic FMR1‐interacting protein 2 (CYFIP2) gene, which was recently identified in individuals diagnosed with West syndrome, a developmental and epileptic encephalopathy. The Cyfip2+/R87C mice recapitulated many neurological and neurobehavioral phenotypes of the patients, including spasmlike movements, microcephaly, and impaired social communication. Age‐progressive cytoarchitectural disorganization and gliosis were also identified in the hippocampus of Cyfip2+/R87C mice. Beyond identifying a decrease in CYFIP2 protein levels in the Cyfip2+/R87C brains, we demonstrated that the p.Arg87Cys variant enhances ubiquitination and proteasomal degradation of CYFIP2. ANN NEUROL 2023;93:155–163
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A knock-in mouse model of the p.Arg87Cys variant recapitulated many neurological and neurobehavioral phenotypes found in patients with this variant.
“A knock-in mouse model of the p.Arg87Cys variant recapitulated many neurological and neurobehavioral phenotypes found in patients with this variant120.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [120]
Disorganization of neuronal layers and gliosis in the brain were observed in the p.Arg87Cys knock-in mice.
“In addition, disorganization of the neuronal layers and gliosis in the brain were observed in the knock-in mice.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [120]
The Arg87Cys variant enhances ubiquitination and proteasomal degradation of CYFIP2 in cultured cells and mouse brains, establishing a loss-of-function mechanism involving Arg87 variants.
“The Arg87Cys variant enhances the ubiquitination and proteasomal degradation of CYFIP2 in cultured cells and mouse brains, establishing an LoF mechanism involving Arg87 variants120.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [120]
The loss-of-function mechanism of CYFIP2 was further supported by the finding of protein instability of CYFIP2 variants in cells and in the brain.
“However, the LoF mechanism of CYFIP2 was further supported by the finding of protein instability of CYFIP2 variants in cells119 and in the brain120.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [120]
Cites
Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy
Zhao, X., Liao, Y., Morgan, S., Mathur, R., Feustel, P., Mazurkiewicz, J., Qian, J., Chang, J., Mathern, G. W., Adamo, M. A., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.004 · Cited by 190 · see citing works
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The WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
Self-citation
- Authors
- Kang, M., Zhang, Y., Kang, H. R., Kim, S., Ma, R., Yi, Y., Lee, S., Kim, Y., Li, H., Jin, C., Lee, D., Kim, E., & Han, K.
- Affiliations
- Korea Advanced Institute of Science and Technology (KR)
- Korea University (KR)
- Institute for Basic Science (KR)
- Corresponding author
- Kim, Eunjoon
- Han, Kihoon
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2022-10-26
- Volume
- 93
- Issue
- 1
- Pages
- 155-163
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W4306411843
- Cited by
- 17
- References
- 1
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 3
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Institute for Basic Science (IBS‐R002‐D1)
- Korea University (K2118761)
- National Research Foundation of Korea (2018M3C7A1024603, 2021R1A2C4001429)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- CYFIP2, West syndrome, developmental and epileptic encephalopathy, knockin mouse model, protein degradation, ubiquitination, proteasomal degradation, microcephaly, social communication deficits
- MeSH terms
- Animals, Brain, Hippocampus, Spasms, Infantile, Adaptor Proteins, Signal Transducing, Mice, Fragile X Messenger Ribonucleoprotein 1
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