CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2

Muwon Kang; Yinhua Zhang; Hyae Rim Kang; Seoyeong Kim; Ruiying Ma; Yunho Yi; Seungjoon Lee; Yoonhee Kim; Huiling Li; Chunmei Jin; Dongmin Lee; Eunjoon Kim; Kihoon Han

doi:10.1002/ana.26535

CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2

Muwon Kang, Yinhua Zhang, Hyae Rim Kang, Seoyeong Kim, Ruiying Ma, Yunho Yi, Seungjoon Lee, Yoonhee Kim, Huiling Li, Chunmei Jin, Dongmin Lee, Eunjoon Kim, Kihoon Han

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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.

Original language	English
Pages (from-to)	155-163
Number of pages	9
Journal	Annals of Neurology
Volume	93
Issue number	1
DOIs	https://doi.org/10.1002/ana.26535
Publication status	Published - 2023 Jan

Bibliographical note

Funding Information:
This study was supported by National Research Foundation of Korea (NRF) grants funded by the Korea Government Ministry of Science and Information and Communications Technology (NRF‐2018M3C7A1024603 and NRF‐2021R1A2C4001429 to K.H.), by the Institute for Basic Science (IBS‐R002‐D1 to E.K.), and by a Korea University grant (K2118761 to K.H.).

Publisher Copyright:
© 2022 American Neurological Association.

ASJC Scopus subject areas

Neurology
Clinical Neurology

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@article{12b6d7c1e48e432b979a3c15010970c7,

title = "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.",

author = "Muwon Kang and Yinhua Zhang and Kang, {Hyae Rim} and Seoyeong Kim and Ruiying Ma and Yunho Yi and Seungjoon Lee and Yoonhee Kim and Huiling Li and Chunmei Jin and Dongmin Lee and Eunjoon Kim and Kihoon Han",

note = "Funding Information: This study was supported by National Research Foundation of Korea (NRF) grants funded by the Korea Government Ministry of Science and Information and Communications Technology (NRF‐2018M3C7A1024603 and NRF‐2021R1A2C4001429 to K.H.), by the Institute for Basic Science (IBS‐R002‐D1 to E.K.), and by a Korea University grant (K2118761 to K.H.). Publisher Copyright: {\textcopyright} 2022 American Neurological Association.",

year = "2023",

month = jan,

doi = "10.1002/ana.26535",

language = "English",

volume = "93",

pages = "155--163",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

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T1 - CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2

AU - Kang, Muwon

AU - Zhang, Yinhua

AU - Kang, Hyae Rim

AU - Kim, Seoyeong

AU - Ma, Ruiying

AU - Yi, Yunho

AU - Lee, Seungjoon

AU - Kim, Yoonhee

AU - Li, Huiling

AU - Jin, Chunmei

AU - Lee, Dongmin

AU - Kim, Eunjoon

AU - Han, Kihoon

N1 - Funding Information: This study was supported by National Research Foundation of Korea (NRF) grants funded by the Korea Government Ministry of Science and Information and Communications Technology (NRF‐2018M3C7A1024603 and NRF‐2021R1A2C4001429 to K.H.), by the Institute for Basic Science (IBS‐R002‐D1 to E.K.), and by a Korea University grant (K2118761 to K.H.). Publisher Copyright: © 2022 American Neurological Association.

PY - 2023/1

Y1 - 2023/1

N2 - 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.

AB - 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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VL - 93

SP - 155

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JO - Annals of Neurology

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CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2

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