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Mitochondrial genome variations are associated with amyotrophic lateral sclerosis in patients from mainland China

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Abstract

Background

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder. Mitochondrial dysfunction is involved in the complex pathophysiology of ALS; however, the role of mitochondrial DNA (mtDNA) variants in ALS is poorly understood. We aimed to elucidate the role of mtDNA variants in the pathogenesis of ALS.

Methods

The mitochondrial haplogroups of 585 ALS patients and 371 healthy controls were determined; 38 ALS patients and 42 controls underwent long-range polymerase chain reaction combined with next-generation sequencing technology to analyze whole mitochondrial genome variants.

Results

A higher percentage of variants accumulated in ALS patients than in controls. Analysis of coding region variations that were further stratified by mtDNA genes revealed that nonsynonymous variants were more vulnerable in ALS patients than in controls, particularly in the ND4L, ND5, and ATP8 genes. Moreover, pathogenic nonsynonymous variants tended to over-represent in ALS patients. Unsurprisingly, nonsynonymous variants were not related to the phenotype. Haplogroup analysis did not found evidence of association between haplogroups with the risk of ALS, however, patients belonging to haplogroup Y and M7c were prone to develop later onset of ALS.

Conclusions

This is the first study to profile mtDNA variants in ALS patients from mainland China. Our results suggest that an increase in the number of nonsynonymous variants is linked to the pathogenesis of ALS. Moreover, haplogroup Y and M7c may modulate the clinical expression of ALS. Our findings provide independent, albeit limited, evidence for the role of mtDNA in the pathogenesis of ALS.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful to the participating patients for their involvement.

Funding

This work was supported by the National Key Research and Development Program of China (#2018YFC1312003); the Program of National Natural Science Foundation of China (#81671120, 81300981); and Natural Science Fund for Distinguished Young Scholars of Hunan province, China (#2020JJ2057); the Project Program of National Clinical Research Center for Geriatric Disorders (Xiangya Hospital) (#2020LNJJ13); and the Degree & Postgraduate Education Reform Project of Central South University (#2020JGB136).

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Authors and Affiliations

  1. Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, Hunan, People’s Republic of China

    Jie Ni, Zhen Liu, Yanchun Yuan, Wanzhen Li, Yiting Hu, Pan Liu, Xiaorong Hou, Xiangyu Zhu, Xuxiong Tang, Xuan Hou, Juan Du, Hong Jiang, Lu Shen, Beisha Tang & Junling Wang

  2. Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China

    Mingyu liang & Siqi Zheng

  3. Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China

    Jianguang Tang

  4. Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 410008, People’s Republic of China

    Hong Jiang, Lu Shen, Beisha Tang & Junling Wang

  5. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, People’s Republic of China

    Hong Jiang, Lu Shen, Beisha Tang & Junling Wang

  6. National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China

    Hong Jiang, Lu Shen, Beisha Tang & Junling Wang

Authors
  1. Jie Ni
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  2. Zhen Liu
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  3. Yanchun Yuan
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  4. Wanzhen Li
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  5. Yiting Hu
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  6. Pan Liu
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  7. Xiaorong Hou
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  8. Xiangyu Zhu
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  9. Xuxiong Tang
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  10. Mingyu liang
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  11. Siqi Zheng
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  12. Xuan Hou
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  13. Juan Du
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  15. Hong Jiang
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  16. Lu Shen
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  17. Beisha Tang
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  18. Junling Wang
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Contributions

Formal analysis: JN; Investigation: JN, ZL, YY; Methodology: JN; Writing—original draft: JN; Data curation: JN, ZL, YY, WLi, YH, PL, XH, XZ, XT, ML, SZ; Writing—review & editing: XH, JD, JW; Supervision: JT, HJ, LS, BT, JW; Conceptualization: JW; Funding acquisition: JW.

Corresponding author

Correspondence to Junling Wang.

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The authors report no actual or potential conflicts of interest.

Ethics approval

The study was approved by the Ethics Committee of Xiangya Hospital, Central South University.

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Written informed consent was obtained from all subjects.

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Written informed consent for publication was obtained from all participants.

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Ni, J., Liu, Z., Yuan, Y. et al. Mitochondrial genome variations are associated with amyotrophic lateral sclerosis in patients from mainland China. J Neurol 269, 805–814 (2022). https://doi.org/10.1007/s00415-021-10659-7

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  • DOI: https://doi.org/10.1007/s00415-021-10659-7

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