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Mutations in aARS genes revealed by targeted next-generation sequencing in patients with mitochondrial diseases

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Abstract

Mitochondrial diseases are a clinically heterogeneous group of multisystemic disorders that arise as a result of various mitochondrial dysfunctions. Autosomal recessive aARS deficiencies represent a rapidly growing group of severe rare inherited mitochondrial diseases, involving multiple organs, and currently without curative option. They might be related to defects of mitochondrial aminoacyl t-RNA synthetases (mtARS) that are ubiquitous enzymes involved in mitochondrial aminoacylation and the translation process. Here, using NGS analysis of 281 nuclear genes encoding mitochondrial proteins, we identified 4 variants in different mtARS in three patients from unrelated Tunisian families, with clinical features of mitochondrial disorders. Two homozygous variants were found in KARS (c.683C>T) and AARS2 (c.1150-4C>G), respectively in two patients, while two heterozygous variants in EARS2 (c.486-7C>G) and DARS2 (c.1456C>T) were concomitantly found in the third patient. Bio-informatics investigations predicted their pathogenicity and deleterious effects on pre-mRNA splicing and on protein stability. Thus, our results suggest that mtARS mutations are common in Tunisian patients with mitochondrial diseases.

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Acknowledgements

We would like to thank all the member of the family for their cooperationin the present study. This work was supported by the Ministryof Higher Education and Scientific Research in Tunisia, University of Sfax.Weacknowledge the support from the National Institute of Health and Medical Research (INSERM), Centre National de la Recherche Scientifique (CNRS), the Université d’Angers, the UniversityHospital of Angers, the Région Pays de Loire and Angers Loire Métropole.

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Author notes

  1. Majida Charif and Lamia Sfaihi have contributed equally to this work.

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, Emna Mkaouar-Rebai & Faiza Fakhfakh

  2. MitoLab Team, Institut MitoVasc, UMR CNRS6015, INSERM U1083, Angers University, Angers, France

    Majida Charif, Valerie Desquiret-Dumas, Céline Bris, David Goudenège, Agnès Guichet, Dominique Bonneau, Vincent Procaccio, Pascal Reynier, Patrizia Amati-Bonneau & Guy Lenaers

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

    Lamia Sfaihi & Mongia Hachicha

  4. Departments of Biochemistry and Genetics, University Hospital Angers, Angers, France

    Valerie Desquiret-Dumas, Céline Bris, David Goudenège, Agnès Guichet, Dominique Bonneau, Vincent Procaccio, Pascal Reynier & Patrizia Amati-Bonneau

  5. Departments of Pathology, University Hospital Habib Bourguiba, Sfax, Tunisia

    Rim Kallel

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

    Majida Charif

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  1. Rahma Felhi
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Contributions

Felhi, Charif, Fakhfakh and Lenaers 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. Clinical investigation and phenotyping: Lamia sfaihi, Rim Kalleland Mongia Hachicha. Analysis or interpretation of data: Felhi, Charif, Emna mkaouer-Rebai, Desquiret-Dumas, Bris, Goudenège, Guichet, Lenaers and Fakhfakh. Draft of the manuscript: Felhi, Charif, Sfaihi, Fakhfakh and Lenaers. Critical revision of the manuscript for important intellectual content: Bonneau, Procaccio, Reynier, Amati-Bonneau, Lenaers and Fakhfakh.

Corresponding authors

Correspondence to Rahma Felhi or Faiza Fakhfakh.

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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., Charif, M., Sfaihi, L. et al. Mutations in aARS genes revealed by targeted next-generation sequencing in patients with mitochondrial diseases. Mol Biol Rep 47, 3779–3787 (2020). https://doi.org/10.1007/s11033-020-05425-3

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