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Vitamin B1 deficiency leads to high oxidative stress and mtDNA depletion caused by SLC19A3 mutation in consanguineous family with Leigh syndrome

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Abstract

Leigh syndrome (LS) and Leigh-like spectrum are the most common infantile mitochondrial disorders characterized by heterogeneous neurologic and metabolic manifestations. Pathogenic variants in SLC carriers are frequently reported in LS given their important role in transporting various solutes across the blood–brain barrier. SLC19A3 (THTR2) is one of these carriers transporting vitamin-B1 (vitB1, thiamine) into the cell. Targeted NGS of nuclear genes involved in mitochondrial diseases was performed in a patient belonging to a consanguineous Tunisian family with LS and revealed a homozygous c.1264 A > G (p.T422A) variant in SLC19A3. Molecular docking revealed that the p.T422A aa change is located at a key position interacting with vitB1 and causes conformational changes compromising vitB1 import. We further disclosed decreased plasma antioxidant activities of CAT, SOD and GSH enzymes, and a 42% decrease of the mtDNA copy number in patient blood.

Altogether, our results disclose that the c.1264 A > G (p.T422A) variant in SLC19A3 affects vitB1 transport, induces a mtDNA depletion and reduces the expression level of oxidative stress enzymes, altogether contributing to the LS phenotype of the patient.

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Acknowledgements

We would like to thank all the member of the family for their cooperation in the present study. This work was supported by the Ministry of Higher Education and Scientific Research in Tunisia, University of Sfax. We acknowledge the support from the INSERM and CNRS, France, the Universty of Angers, the University Hospital of Angers, the Pays of Loire Region, France.

Funding

This work was supported by the Ministry of Higher Education and the Scientific Research in Tunisia.

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Author notes

  1. Lamia Sfaihi and Majida Charif are equal contributors.

Authors and Affiliations

  1. Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Route Soukra. Km 3., Sfax, Tunisia

    Rahma Felhi & Faiza Fakhfakh

  2. Departments of Pediatry, University Hospital Hedi Chaker, Sfax, Tunisia

    Lamia Sfaihi & Thouraya Kamoun

  3. Genetics and Immuno-Cell Therapy Team, Mohammed First University, Oujda, Morocco

    Majida Charif

  4. Laboratory of Molecular and Cellular Screening Processes, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia

    Fakher Frikha

  5. Laboratory of Animal Eco-Physiology, Faculty of Sciences of Sfax, Sfax, Tunisia

    Nissaf Aoiadni

  6. Université d’Angers, Unité MitoVasc, INSERM U1083, CNRS 6015, SFR- ICAT, Equipe MitoLab, 49933, Angers, France

    Guy Lenaers

  7. Service de Neurologie, CHU d’Angers, 49100, Angers, France

    Guy Lenaers

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Contributions

Felhi R, Charif M, Lenaers G and Fakhfakh F had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Sfaihi L, Kamoun TH: Clinical investigations. Fakher F: molecular docking. Aoiadni N: oxidative stress. Analysis or interpretation of data: Felhi R, and Fakhfakh F. Draft of the manuscript: Felhi F, Charif M, Lenaers L and Fakhfakh F.

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Correspondence to Rahma Felhi.

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The study was conducted in accordance with the principles stated in the Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects, Helsinki, Finland, 1964, and as amended in Fortaleza, Brazil, 2013. The study design was approved by the committee on research ethics of the University of Sfax, Tunisia.

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Felhi, R., Sfaihi, L., Charif, M. et al. Vitamin B1 deficiency leads to high oxidative stress and mtDNA depletion caused by SLC19A3 mutation in consanguineous family with Leigh syndrome. Metab Brain Dis 38, 2489–2497 (2023). https://doi.org/10.1007/s11011-023-01280-w

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