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.
Molecular docking
Molecular simulation
NAXE gene
PEBEL syndrome
Journal
Neurogenetics
ISSN: 1364-6753
Titre abrégé: Neurogenetics
Pays: United States
ID NLM: 9709714
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
03
05
2022
accepted:
04
07
2022
pubmed:
13
7
2022
medline:
18
11
2022
entrez:
12
7
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35819538
doi: 10.1007/s10048-022-00696-3
pii: 10.1007/s10048-022-00696-3
doi:
Substances chimiques
NAD
0U46U6E8UK
NAXE protein, human
EC 5.1.-
Racemases and Epimerases
EC 5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
257-270Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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