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Han family with essential tremor caused by the P421L variant of the TENM4 gene in China

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Abstract

Background

Essential tremor (ET) is an autosomal dominant inheritance disorder. Mutations in fusion sarcoma (FUS), mitochondrial serine peptidase 2 (HTRA2), teneurin transmembrane protein 4 (TENM4), sortilin1 (SORT1), SCN11A, and notch2N-terminal-like (NOTCH2NLC) genes are associated with familial ET.

Methods

A proband with ET was tested using whole-exome sequencing and repeat-primed polymerase chain reaction. Subsequently, the family members were screened for the suspected mutation, and the results were verified using Sanger sequencing. The relationship between pedigree and phenotype was also analyzed, and structural and functional changes in the variants were predicted using bioinformatics analysis.

Results

In a family with ET, the proband (III4) and the proband’s father (II1), grandfather (I1), uncle (II2), and cousin (III5) all presented with involuntary tremors of both upper limbs. The responsible mutation was identified as TENM4 c.1262C > T (p.P421L), which showed genetic co-segregation in the family survey. AlphaFold predicted a change in the spatial position of TENM4 after the P421L mutation, which may have affected its stability. AlphaFold also predicted P421L to be a deleterious variation, which would lead to lower degrees of freedom of the TENM4 protein, thereby affecting the protein’s structure and stability. According to the bioinformatics analysis, TENM4 (p.P421L) may reduce the signal reaching the nucleus by affecting the expression of TENM4 messenger RNA (mRNA), thereby impairing the normal oligodendrocyte differentiation process and leading to impaired myelination.

Conclusion

This study revealed that the TENM4 (p.P421L) pathogenic missense variation was responsible for ET in the proband.

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Data availability

The original contributions presented in this study are included in the article/supplementary material, and further inquiries can be directed to the corresponding authors.

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Funding

This work was supported by the Fujian Province Natural Science Fund Project (2021 J02053, 2021 J01704), Fujian Province Medical Innovation Foundation (2019-CXB-4), and Special Research Foundation of Fujian Provincial Department of Finance, China (2020–822, 2021–917). Startup Fund for Scientific Research, Fujian Medical University (2019QH1072). Nationally famous and old Chinese medicine experts (Zhang Xuemei, Yan Xiaohua) participated in the inheritance studio construction project.

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Author notes

  1. Wu Chi, Min Wu, and Han-lu Wang contributed equally.

Authors and Affiliations

  1. Fujian Provincial HospitalShengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China

    Wu Chi, Min Wu, Han-lu Wang, Qiu-yan Wu, Yan-ping Zhang, Ya-nan Hu, Yao-bin Zhu, Xin-fu Lin, Jie-wei Luo & Yun-fei Li

  2. Emergency Department, Fujian Provincial Hospital, Fuzhou, 350001, China

    Wu Chi

  3. Fujian Provincial Key Laboratory of Emergency Medicine, Fujian Provincial Institute of Emergency MedicineFujian Emergency Medical Center, Fuzhou, 350001, China

    Wu Chi

  4. Department of Traditional Chinese Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China

    Yao-bin Zhu

  5. Department of Pediatrics, Fujian Provincial Hospital, Fuzhou, 350001, China

    Xin-fu Lin

  6. Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Fuzhou, 350001, China

    Ting Chen & Jie-wei Luo

  7. Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China

    Xing-lin Ruan

  8. Department of Neurology, Fujian Provincial Hospital, Fuzhou, 350001, China

    Yun-fei Li

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  1. Wu Chi
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Contributions

WC, MW, and H-LW acquired, analyzed, and interpreted the clinical data. MW, Q-YW, Y-PZ, and Y-NH drafted the manuscript. Y-BZ, X-LR, and X-FL critically revised the manuscript. JWL, TC, and Y-FL designed and supervised the study. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Ting Chen, Jie-wei Luo, Xing-lin Ruan or Yun-fei Li.

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Ethics approval and consent to participate

All procedures were performed in accordance with the tenets of the Declaration of Helsinki and the study was approved by the Ethics Committee of Fujian Provincial Hospital, Fuzhou, China. All participants and legal guardians of the minors involved in the study provided written informed consent.

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The authors declare no competing interests.

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Chi, W., Wu, M., Wang, Hl. et al. Han family with essential tremor caused by the P421L variant of the TENM4 gene in China. Neurol Sci 44, 2003–2015 (2023). https://doi.org/10.1007/s10072-023-06603-4

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