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Mitochondrial disease patients with novel ND4 12058A > C and ND1 m.3911A > G variations: implications for a role in the phenotype following a bioinformatic investigation

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Abstract

Mitochondrial diseases include a wide group of clinically heterogeneous disorders caused by a dysfunction of the mitochondrial respiratory chain and can be related to mutations in nuclear or mitochondrial DNA genes. In the present report, we performed a whole mitochondrial genome screening in two patients with clinical features of mitochondrial diseases. Mutational analysis revealed the presence of two undescribed heteroplasmic mitochondrial variations, the m.3911A > G (E202G) variant in the MT-ND1 gene found in two patients (P1 and P2) and the m.12058A > C (E433D) pathogenic variant in the MT-ND4 gene present only in patient P2 who had a more severe phenotype. These two substitutions were predicted to be damaging by several bioinformatics tools and lead to amino acid changes in two conserved residues localized in two important functional domains of the mitochondrial subunits of complex I. Furthermore, the 3D modeling suggested that the two amino acid changes could therefore alter the structure of the two subunits and may decrease the stability and the function of complex I. The two described pathogenic variants found in patient P2 could act synergically and alter the complex I function by affecting the proton pumping processes and the energy production and then could explain the severe phenotype compared to patient P1 presenting only the E202G substitution in ND1.

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Acknowledgements

We thank patients and their families for their cooperation in the present study. This work was supported by The Ministry of Higher Education and the Scientific Research in Tunisia.

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Authors and Affiliations

  1. Molecular and Functional Genetics Laboratory, Department of Life Science, Faculty of Sciences of Sfax, The University of Sfax, Sfax, Tunisia

    Emna Mkaouar-Rebai, Marwa Ammar, Olfa Alila-Fersi, Marwa Maalej, Rahma Felhi & Faiza Fakhfakh

  2. Department of Pediatrics, C.H.U. Hedi Chaker, Sfax, Tunisia

    Lamia Sfaihi & Mongia Hachicha

Authors
  1. Emna Mkaouar-Rebai
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  2. Marwa Ammar
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  3. Lamia Sfaihi
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  6. Rahma Felhi
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Contributions

All authors contributed to the study’s conception and design. Material preparation, data collection and analysis were performed by EMR and MA. The first draft of the manuscript was written by EMR and all authors commented on previous versions of the manuscript. RF, OAF and MM, contributed to molecular genetic studies. LS, IC, MH provided the clinical explorations, supervised and conceived the clinical part of the manuscript. FF supervised and conceived the molecular genetic studies and drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Emna Mkaouar-Rebai.

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The authors declare that they have no conflicts of interest or financial relationships relevant to this article to disclose.

Ethical approval

The study design was approved by the committee on research ethics: Comité de Protection des Personnes SUD (C.P.P.SUD) and we declare that all procedures performed in this study involving human participants were conducted in accordance with the principles stated in the Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects, Helsinki, Finland, 1964.

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Mkaouar-Rebai, E., Ammar, M., Sfaihi, L. et al. Mitochondrial disease patients with novel ND4 12058A > C and ND1 m.3911A > G variations: implications for a role in the phenotype following a bioinformatic investigation. Mol Biol Rep 48, 4373–4382 (2021). https://doi.org/10.1007/s11033-021-06452-4

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  • DOI: https://doi.org/10.1007/s11033-021-06452-4

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