Abstract
Progressive encephalopathy with brain edema and/or leukoencephalopathy, PEBEL1, is a severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration associated with a febrile illness. PEBEL1 is a lethal encephalopathy caused by NAXE gene mutations. Here we report a 6-month-old boy with mitochondrial encephalomyopathy from a consanguineous family. Molecular analysis was performed using whole-exome sequencing followed by segregation analysis. In addition, in silico prediction tools and molecular dynamic approaches were used to predict the structural effect of the mutation. Furthermore, molecular docking of the substrate NADP in both wild-type and mutated NAXE protein was carried out. Molecular analysis revealed the presence of the novel homozygous mutation c.641 T > A (p. Ile214Asn) in the NAXE gene, located at the NAD (P)H hydrate epimerase domain. In addition, bioinformatics analyses and molecular dynamics revealed that p. Ile214Asn mutation could affect the structure, stability, and compactness of the NAXE protein. Moreover, the result of the molecular docking showed that the p. Ile214Asn mutation leads to conformational changes in the catalytic cavity, thus modifying interaction with the substrate and restricting its access. We also compared the phenotype of our patient with those of previously reported cases with PEBEL syndrome. All bioinformatics findings provide evidence that the NAXE variant Asn214 disrupts NAXE protein functionality leading to an insufficient NAD (P)HX repair system and the development of clinical features of PEBEL1 syndrome in our patient. To our knowledge, our case is the 21st case of PEBEL1 patient worldwide and the first case in North Africa.
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The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors would like to thank the parents of the patient for their cooperation in the present study.
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This work was supported by The Ministry of Higher Education and Scientific Research in Tunisia and the University of Sharjah, UAE.
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All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by MM and LS. The first draft of the manuscript was written by MM and all authors commented on previous versions of the manuscript. EMR, OAF, and MK contributed to molecular genetic studies and MA and FF and contributed to bioinformatics data analysis. LS and TK provided the clinical explorations, and supervised and conceived the clinical part of the manuscript. FF and AT supervised and conceived the molecular genetic studies and drafted the manuscript. All authors read and approved the final manuscript.
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The written informed consent was obtained from the parents as legal guardians of the proband. 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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Maalej, M., Sfaihi, L., Ammar, M. et al. Identification of a novel homozygous mutation in NAXE gene associated with early-onset progressive encephalopathy by whole-exome sequencing: in silico protein structure characterization, molecular docking, and dynamic simulation. Neurogenetics 23, 257–270 (2022). https://doi.org/10.1007/s10048-022-00696-3
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DOI: https://doi.org/10.1007/s10048-022-00696-3