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Loss-of-function mutation in DDX53 associated with hereditary spastic paraplegia-like disorder

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Abstract

DEAD-box helicase 53 (DDX53) is a member of the DEAD-box protein family of RNA helicases. Unlike other family members that are responsible for RNA metabolism, the biological function of DDX53 and its impact on the human condition are unclear. Herein, we found a full-length DDX53 deletion mutation in a hereditary spastic paraplegia-like (HSP-like) patient with lower extremity spasticity, walking disorder, visual impairment, and lateral ventricular white matter lesions. Bioinformatic analysis revealed that DDX53 was mainly expressed in the cerebellar cortex and may function as a tissue-specific RNA helicase. Transcriptome analysis showed that the expression of multiple brain-associated genes involved in synapse organization, neuron function, and neuromuscular junctions was affected by DDX53 depletion. Moreover, RNA immunoprecipitation sequencing (RIP-seq) analysis showed that DDX53 interacted with 176 genes, and 96 of these genes were associated with the execution of neurofunction, particularly in the regulation of cell projection organization and nervous system development. Collectively, although a more specified cell or animal model is required to fully understand the functional role of DDX53 in the human brain, we report for the first time that the patient with DDX53 defects exhibits HSP-like symptoms and that DDX53 is essential for maintaining neuronal function, with loss-of-function mutation in DDX53 potentially leading to HSP due to impaired RNA metabolism in the nervous system.

Key messages

  • DDX53 deficiency was first reported to be associated with HSP disorder.

  • DDX53 exhibited minimal impact on mitochondrial function.

  • DDX53 impaired RNA metabolism in the nervous system.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Funding

This work was supported by grants from the National Natural Science Foundation of China-excellent young scientists fund (No. 82222043), the “Pioneer” and “Leading Goose” R&D Program of Zhejiang Province (No. 2024C03152), the Natural Science Foundation of China (Nos. 82172322 and 82302636), the Zhejiang Provincial Natural Science Foundation (No. LQ23H200001), the Scientific Research Fund of Zhejiang Provincial Education Department (No. Y202249698), and the Science and Technology Bureau of Wenzhou (No. Y2023089).

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Author notes

  1. Xiangshu Yuan, Ya Wang, and Xiyuan Li contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Xiangshu Yuan, Ya Wang, Sheng Zhong, Danyi Zhou, Xianlong Lin & Hezhi Fang

  2. Baylor Genetics, Houston, TX, 77030, USA

    Xiyuan Li

  3. Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China

    Yanling Yang

  4. Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, 322100, Zhejiang, China

    Maofeng Wang

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  1. Xiangshu Yuan
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Contributions

All authors contributed to the study conception and design. HF and YY conceived the study and designed the experiments. XY, YW, XL, SZ, DZ, and XL performed the experiments and analyzed data. MW conducted the analysis of transcriptomics and RNA immunoprecipitation sequencing data and provided critical input on the study. The manuscript was written by XY and YW with input from all the authors.

Corresponding authors

Correspondence to Hezhi Fang, Yanling Yang or Maofeng Wang.

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Informed consent was obtained from the subjects enrolled in this study, and the study was approved by the Ethics Committee of Peking University First Hospital (No. 2017-217).

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Yuan, X., Wang, Y., Li, X. et al. Loss-of-function mutation in DDX53 associated with hereditary spastic paraplegia-like disorder. J Mol Med (2024). https://doi.org/10.1007/s00109-024-02454-4

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