Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease characterized by bradykinesia, rigidity, and tremor. However, familial PD caused by single-gene mutations remain relatively rare. Herein, we described a Chinese family affected by PD, which associated with a missense heterozygous glucocerebrosidase 1 (GBA1) mutation (c.231C > G). Clinical data on the proband and her family members were collected. Brain MRI showed no difference between affected and unaffected family members. Whole-exome sequencing (WES) was performed to identify the pathogenic mutation. WES revealed that the proband carried a missense mutation (c.231C > G) in GBA1 gene, which was considered to be associated with PD in this family. Sanger sequencing and co-segregation analyses were used to validate the mutation. Bioinformatics analysis indicated that the mutation was predicted to be damaging. In vitro functional analyses were performed to investigated the mutant gene. A decrease in mRNA and protein expression was observed in HEK293T cells transfected with mutant plasmids. The GBA1 c.231C > G mutation caused a decreased GBA1 concentration and enzyme activity. In conclusion, a loss of function mutation (c.231C > G) in GBA1 was identified in a Chinese PD family and was confirmed to be pathogenic through functional studies. This study help the family members understand the disease progression and provide a new example for studying the pathogenesis of GBA1-associated Parkinson disease.
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The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We thank the patients and their family members for consenting to this research. This work was supported by the National Natural Science Foundation of China (32170617, 31970558), National Key S&T Special Projects (2021YFC100530) and the Natural Science Foundation of Guangdong Province of China (2020A1515010308, 2020B1515120009, 2022A1515012621).
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Dejie Chen, Yingchun Zheng, Fu Xiong and Quanxi Su: study concept and design. Dejie Chen, Fu Xiong and Quanxi Su wrote original draft. Yingchun Zheng, Guilian Zhang, Yuanbing Huang, Boyang Zheng, Jian Zhang: data acquisition and analysis. All authors contributed to further revisions of the manuscript draft and approved the final version.
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Approval was obtained from the Ethics Committee of Yunfu People’s Hospital, an affiliate of Southern Medical University. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants.
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Chen, D., Zheng, Y., Zhang, G. et al. The loss of function GBA1 c.231C > G mutation associated with Parkinson disease. J Neural Transm 130, 905–913 (2023). https://doi.org/10.1007/s00702-023-02651-4
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DOI: https://doi.org/10.1007/s00702-023-02651-4