<i>KCTD10</i> p.C124W variant contributes to schizophrenia by attenuating LLPS-mediated synapse formation

KCTD10, a member of the potassium channel tetramerization domain (KCTD) family, is implicated in neuropsychiatric disorders and functions as a substrate recognition component within the RING-type ubiquitin ligase complex. A rare de novo variant of KCTD10, p.C124W, was identified in schizophrenia cases, yet its underlying pathogenesis remains unexplored. Here, we demonstrate that heterozygous KCTD10 C124W mice display pronounced synaptic abnormalities and exhibit schizophrenia-like behaviors. Mechanistically, we reveal that KCTD10 undergoes liquid-liquid phase separation (LLPS), a process orchestrated by its intrinsically disordered region (IDR). p.C124W mutation disrupts this LLPS capability, leading to diminished degradation of RHOB and subsequent excessive accumulation in the postsynaptic density fractions. Notably, neither IDR deletion nor p.C124W mutation in KCTD10 mitigates the synaptic abnormalities caused by <i>Kctd10</i> deficiency. Thus, our findings implicate that LLPS may be associated with the pathogenesis of KCTD10-associated brain disorders and highlight the potential of targeting RHOB as a therapeutic strategy for diseases linked to mutations in KCTD10 or RHOB.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-11-20
DOI
https://doi.org/10.1073/pnas.2400464121
Citations
4
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
0.94

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article

KCTD10 p.C124W variant contributes to schizophrenia by attenuating LLPS-mediated synapse formation

Pan Liu, Qingfeng Wu, Guozhong Li, Zhiheng Xu et al.
4 citations
Proceedings of the National Academy of Sciences
RNA Research and Splicing
0.94
article

KCTD10 p.C124W variant contributes to schizophrenia by attenuating LLPS-mediated synapse formation

Pan Liu, Qingfeng Wu, Guozhong Li, Zhiheng Xu, L Liu, Zhengmao Hu, Ling Yuan, Yuanhang Yao, Yaqing Wang, Hui Guo, Faxiang Li, Zhengrong Zhou, Kun Xia, Jia‐Da Li, Mingzhen Bu, Xiaowei Chen, Xiangyu Li, Jun Guan, Tiantian Ma, Jianbo Cheng, Kefu Liu, Bing Lang, Xiaoqing Peng, Chenjun Mu, Manpei Tang, Han Chen
article en
4 citations

Abstract

KCTD10, a member of the potassium channel tetramerization domain (KCTD) family, is implicated in neuropsychiatric disorders and functions as a substrate recognition component within the RING-type ubiquitin ligase complex. A rare de novo variant of KCTD10, p.C124W, was identified in schizophrenia cases, yet its underlying pathogenesis remains unexplored. Here, we demonstrate that heterozygous KCTD10 C124W mice display pronounced synaptic abnormalities and exhibit schizophrenia-like behaviors. Mechanistically, we reveal that KCTD10 undergoes liquid-liquid phase separation (LLPS), a process orchestrated by its intrinsically disordered region (IDR). p.C124W mutation disrupts this LLPS capability, leading to diminished degradation of RHOB and subsequent excessive accumulation in the postsynaptic density fractions. Notably, neither IDR deletion nor p.C124W mutation in KCTD10 mitigates the synaptic abnormalities caused by <i>Kctd10</i> deficiency. Thus, our findings implicate that LLPS may be associated with the pathogenesis of KCTD10-associated brain disorders and highlight the potential of targeting RHOB as a therapeutic strategy for diseases linked to mutations in KCTD10 or RHOB.

Proceedings of the National Academy of SciencesVol. 121(48)
Central South University (CN), Capital Medical University (CN), Peking University (CN), Shantou University (CN), Shantou University Medical College (CN), Institute of Genetics and Developmental Biology (CN), Second Xiangya Hospital of Central South University (CN), Center for Life Sciences (CN), University of Chinese Academy of Sciences (CN)
National Natural Science Foundation of China, Natural Science Foundation of Hunan Province
Openalex Percentile: Top 25%
RNA Research and Splicing
0.94
DOIOpen Access PDFOpenAlex
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