CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2
Muwon Kang BSc
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea
Search for more papers by this authorYinhua Zhang PhD
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorHyae Rim Kang BSc
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorSeoyeong Kim BSc
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea
Search for more papers by this authorRuiying Ma BSc
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorYunho Yi
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Search for more papers by this authorSeungjoon Lee PhD
Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea
Search for more papers by this authorYoonhee Kim MSc
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorHuiling Li BSc
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorChunmei Jin PhD
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorDongmin Lee MD, PhD
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Department of Anatomy, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorCorresponding Author
Eunjoon Kim PhD
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea
Address correspondence to Dr Han, Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea. E-mail: [email protected] and Dr E. Kim, Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea. E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Kihoon Han PhD
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Address correspondence to Dr Han, Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea. E-mail: [email protected] and Dr E. Kim, Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea. E-mail: [email protected]
Search for more papers by this authorMuwon Kang BSc
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea
Search for more papers by this authorYinhua Zhang PhD
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorHyae Rim Kang BSc
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorSeoyeong Kim BSc
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea
Search for more papers by this authorRuiying Ma BSc
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorYunho Yi
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Search for more papers by this authorSeungjoon Lee PhD
Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea
Search for more papers by this authorYoonhee Kim MSc
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorHuiling Li BSc
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorChunmei Jin PhD
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorDongmin Lee MD, PhD
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Department of Anatomy, Korea University College of Medicine, Seoul, Republic of Korea
Search for more papers by this authorCorresponding Author
Eunjoon Kim PhD
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea
Address correspondence to Dr Han, Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea. E-mail: [email protected] and Dr E. Kim, Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea. E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Kihoon Han PhD
Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Address correspondence to Dr Han, Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea. E-mail: [email protected] and Dr E. Kim, Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea. E-mail: [email protected]
Search for more papers by this authorMuwon Kang, Yinhua Zhang, and Hyae Rim Kang share first authorship.
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
Supporting Information
| Filename | Description |
|---|---|
| ana26535-sup-0001-Video.mp4MPEG-4 video, 2.6 MB | VIDEO S1 Digital video recording showing spasmlike movement in a Cyfip2+/R87C mouse at postnatal day 8 (P8). Each pup at P8 was placed in a plastic tray subdivided into smaller compartments. Heating light was provided to maintain body temperature. The Cyfip2+/R87C pup on the far left compartment in the second row shows spontaneous spasmlike movement consisting of extension of 4 limbs followed by jerking movement. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Nakashima M, Kato M, Aoto K, et al. De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy. Ann Neurol 2018; 83: 794–806.
- 2Peng J, Wang Y, He F, et al. Novel West syndrome candidate genes in a Chinese cohort. CNS Neurosci Ther 2018; 24: 1196–1206.
- 3Zhong M, Liao S, Li T, et al. Early diagnosis improving the outcome of an infant with epileptic encephalopathy with cytoplasmic FMRP interacting protein 2 mutation: case report and literature review. Medicine 2019; 98:e17749.
- 4Zweier M, Begemann A, McWalter K, et al. Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures. Eur J Hum Genet 2019; 27: 747–759.
- 5Begemann A, Sticht H, Begtrup A, et al. New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics. Genet Med 2021; 23: 543–554.
- 6Zhang Y, Lee Y, Han K. Neuronal function and dysfunction of CYFIP2: from actin dynamics to early infantile epileptic encephalopathy. BMB Rep 2019; 52: 304–311.
- 7Lee Y, Zhang Y, Ryu JR, et al. Reduced CYFIP2 stability by Arg87 variants causing human neurological disorders. Ann Neurol 2019; 86: 803–805.
- 8Nakashima M, Ogata K, Saitsu H, Matsumoto N. Reply to "Reduced CYFIP2 stability by Arg87 variants causing human neurological disorders". Ann Neurol 2019; 86: 805–806.
- 9Zhang Y, Kang Hyae R, Lee SH, et al. Enhanced prefrontal neuronal activity and social dominance behavior in postnatal forebrain excitatory neuron-specific Cyfip2 knock-out mice. Front Mol Neurosci 2020; 13:574947.
- 10Lee SH, Zhang Y, Park J, et al. Haploinsufficiency of Cyfip2 causes lithium-responsive prefrontal dysfunction. Ann Neurol 2020; 88: 526–543.
- 11Zhao X, Liao Y, Morgan S, et al. Noninflammatory changes of microglia are sufficient to cause epilepsy. Cell Rep 2018; 22: 2080–2093.
- 12Shin W, Kim K, Serraz B, et al. Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice. PLoS Biol 2020; 18:e3000717.
- 13Lee S, Lee E, Kim R, et al. Shank2 deletion in parvalbumin neurons leads to moderate hyperactivity, enhanced self-grooming and suppressed seizure susceptibility in mice. Front Mol Neurosci 2018; 11: 209.
- 14Chen W, Cai ZL, Chao ES, et al. Stxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy. eLife 2020; 19: 9.
- 15Ito-Ishida A, Ure K, Chen H, et al. Loss of MeCP2 in parvalbumin- and somatostatin-expressing neurons in mice leads to distinct Rett syndrome-like phenotypes. Neuron 2015; 88: 651–658.
- 16Lee Y, Zhang Y, Kang H, et al. Epilepsy-and intellectual disability-associated CYFIP2 interacts with both actin regulators and RNA-binding proteins in the neonatal mouse forebrain. Biochem Biophys Res Commun 2020; 529: 1–6.
- 17Schaks M, Reinke M, Witke W, Rottner K. Molecular dissection of neurodevelopmental disorder-causing mutations in CYFIP2. Cell 2020; 9: 1355.
- 18Thom M. Hippocampal sclerosis in epilepsy: a neuropathology review. Neuropathol Appl Neurobiol 2014; 40: 520–543.
- 19Patel DC, Tewari BP, Chaunsali L, Sontheimer H. Neuron-glia interactions in the pathophysiology of epilepsy. Nat Rev Neurosci 2019; 20: 282–297.
- 20Dulla CG. Utilizing animal models of infantile spasms. Epilepsy Curr 2018; 18: 107–112.
Citing Literature
