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.

Autor: Maalej M; Molecular Genetics and Functional Laboratory, Faculty of Science of Sfax, University of Sfax, Sfax, Tunisia. marwamaalej7@gmail.com., Sfaihi L; Department of Pediatrics, Hédi Chaker Hospital, 3029, Sfax, Tunisia.; Faculty of Medecine of Sfax, Avenue Magida Boulila, 3029, Sfax, Tunisia., Ammar M; Molecular Genetics and Functional Laboratory, Faculty of Science of Sfax, University of Sfax, Sfax, Tunisia., Frikha F; Laboratory of Molecular and Cellular Screening Processes (LPCMC), LR15CBS07, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia., Kharrat M; Molecular Genetics and Functional Laboratory, Faculty of Science of Sfax, University of Sfax, Sfax, Tunisia., Alila-Fersi O; Molecular Genetics and Functional Laboratory, Faculty of Science of Sfax, University of Sfax, Sfax, Tunisia., Mkaouar-Rebai E; Molecular Genetics and Functional Laboratory, Faculty of Science of Sfax, University of Sfax, Sfax, Tunisia., Tlili A; Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates., Kammoun T; Department of Pediatrics, Hédi Chaker Hospital, 3029, Sfax, Tunisia.; Faculty of Medecine of Sfax, Avenue Magida Boulila, 3029, Sfax, Tunisia., Fakhfakh F; Molecular Genetics and Functional Laboratory, Faculty of Science of Sfax, University of Sfax, Sfax, Tunisia.
Jazyk: angličtina
Zdroj: Neurogenetics [Neurogenetics] 2022 Oct; Vol. 23 (4), pp. 257-270. Date of Electronic Publication: 2022 Jul 11.
DOI: 10.1007/s10048-022-00696-3
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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