Vitamin B1 deficiency leads to high oxidative stress and mtDNA depletion caused by SLC19A3 mutation in consanguineous family with Leigh syndrome.
Antioxidant
Encephalopathy
Mitochondrial disorder
Molecular docking
Thiamine
Journal
Metabolic brain disease
ISSN: 1573-7365
Titre abrégé: Metab Brain Dis
Pays: United States
ID NLM: 8610370
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
14
06
2023
accepted:
21
08
2023
medline:
18
9
2023
pubmed:
29
8
2023
entrez:
29
8
2023
Statut:
ppublish
Résumé
Leigh syndrome (LS) and Leigh-like spectrum are the most common infantile mitochondrial disorders characterized by heterogeneous neurologic and metabolic manifestations. Pathogenic variants in SLC carriers are frequently reported in LS given their important role in transporting various solutes across the blood-brain barrier. SLC19A3 (THTR2) is one of these carriers transporting vitamin-B1 (vitB1, thiamine) into the cell. Targeted NGS of nuclear genes involved in mitochondrial diseases was performed in a patient belonging to a consanguineous Tunisian family with LS and revealed a homozygous c.1264 A > G (p.T422A) variant in SLC19A3. Molecular docking revealed that the p.T422A aa change is located at a key position interacting with vitB1 and causes conformational changes compromising vitB1 import. We further disclosed decreased plasma antioxidant activities of CAT, SOD and GSH enzymes, and a 42% decrease of the mtDNA copy number in patient blood.Altogether, our results disclose that the c.1264 A > G (p.T422A) variant in SLC19A3 affects vitB1 transport, induces a mtDNA depletion and reduces the expression level of oxidative stress enzymes, altogether contributing to the LS phenotype of the patient.
Identifiants
pubmed: 37642897
doi: 10.1007/s11011-023-01280-w
pii: 10.1007/s11011-023-01280-w
doi:
Substances chimiques
DNA, Mitochondrial
0
Membrane Transport Proteins
0
SLC19A3 protein, human
0
Thiamine
X66NSO3N35
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2489-2497Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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