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A Missense Variant (R239Q) in CCN3 Induces Aberrant Apoptosis in the Developing Mouse Brain
Biomed Sci Letters 2018;24:64-75
Published online June 30, 2018;  https://doi.org/10.15616/BSL.2018.24.2.64
© 2018 The Korean Society For Biomedical Laboratory Sciences.

Hyunduk Kim1,2,§, Hayoung Yang1,§, Dong Kyun Woo3, Sung-Wuk Jang2,† and Sungbo Shim1,†

1Department of Biochemistry, Chungbuk National University, Cheongju 28644, Korea
2Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea
3College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Gyeongnam 52828, Korea
Correspondence to: Sungbo Shim. Department of Biochemistry, Chungbuk National University, Cheongju 28644, Korea.
Tel: +82-43-261-2318, Fax: +82-43-267-2306, e-mail: sungbo@cbnu.ac.kr
Sung-Wuk Jang. Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea.
Tel: +82-2-3010-2088, Fax: +82-2-3010-2088, e-mail: swjang@amc.seoul.kr
§These authors contributed equally to this work.
Received May 29, 2018; Revised June 3, 2018; Accepted June 4, 2018.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
CCN3 (also known as NOV, Nephroblastoma overexpressed) proteins are involved in various pathologies during different developmental stages. We have previously shown that intracellular levels and normal extracellular secretion of CCN3 are important for neuronal differentiation. Furthermore, we demonstrated that a single amino acid in the CCN3 TSP-1 domain is important for extracellular secretion and that palmitoylation of CCN3 is required in this process. However, the effect of abnormal CCN3 accumulation on cells remains to be studied. Here, we found mutations in the TSP-1 domain of CCN3 that led to intracellular accumulation and abnormal aggregation of CCN3. It was observed that this mutation resulted in a phenomenon similar to neurodegeneration when overexpressed in the developing mouse cortex. This mutation also confirmed the activation of apoptotic gene expression in Neuro2a cells. In addition, we confirmed the in vivo transcriptional changes induced by this mutation using microarray analysis. We observed a significant increase in the expression of Anp32a, an apoptosis-related gene. Collectively, these results indicate that a single mutation in CCN3 can lead to abnormal cell death if it shows intracellular accumulation and abnormal aggregation.
Keywords : Point mutation, CCN3, Aggregation, Apoptosis, Neuron