Non-canonical C-terminal variant of MeCP2 R344W exhibits enhanced degradation rate

Yue Chai; Sharon Shui Ying Lee; Amelle Shillington; Xiaoli Du; Catalina Ka Man Fok; Kam Chun Yeung; Gavin Ka Yu Siu; Shiyang Yuan; Zhongyu Zheng; Hayley Wing Sum Tsang; Shen Gu; Yu Chen; Tao Ye; Jacque Pak Kan Ip

doi:10.1016/j.ibneur.2023.09.007

Non-canonical C-terminal variant of MeCP2 R344W exhibits enhanced degradation rate

IBRO Neurosci Rep. 2023 Sep 22:15:218-224. doi: 10.1016/j.ibneur.2023.09.007. eCollection 2023 Dec.

Authors

Yue Chai^{1

2}, Sharon Shui Ying Lee¹, Amelle Shillington³, Xiaoli Du³, Catalina Ka Man Fok¹, Kam Chun Yeung¹, Gavin Ka Yu Siu¹, Shiyang Yuan¹, Zhongyu Zheng¹, Hayley Wing Sum Tsang⁴, Shen Gu^{1

5

6}, Yu Chen^{2

7}, Tao Ye^{2

7}, Jacque Pak Kan Ip^{1

5

6}

Affiliations

¹ School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
² Chinese Academy of Sciences Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Translational Research for Brain Diseases, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.
³ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁴ Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
⁵ Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Hong Kong, China.
⁶ CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
⁷ Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.

Abstract

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by pathogenic variants in the MECP2 gene. While the majority of RTT-causing variants are clustered in the methyl-CpG binding domain and NCoR/SMRT interaction domain, we report a female patient with a functionally uncharacterized MECP2 variant in the C-terminal domain, c.1030C>T (R344W). We functionally characterized MECP2-R344W in terms of protein stability, NCoR/SMRT complex interaction, and protein nuclear localization in vitro. MECP2-R344W cells showed an increased protein degradation rate without significant change in NCoR/SMRT complex interaction and nuclear localization pattern, suggesting that enhanced MECP2 degradation is sufficient to cause a Rett Syndrome-like phenotype. This study highlights the pathogenicity of the C-terminal domain in Rett Syndrome, and demonstrates the potential of targeting MECP2 protein stability as a therapeutic approach.

Keywords: Carboxyl-terminal domain (C-terminal domain); Methyl-CpG binding domain 2 (MECP2); Missense variant; Protein degradation; Protein stability; R344W; Rett Syndrome.