Abstract
Short-chain enoyl-CoA hydratase deficiency (ECHS1D) is a rare congenital metabolic disorder that follows an autosomal recessive inheritance pattern. It is caused by mutations in the ECHS1 gene, which encodes a mitochondrial enzyme involved in the second step of mitochondrial β-oxidation of fatty acids. The main characteristics of the disease are severe developmental delay, regression, seizures, neurodegeneration, high blood lactate, and a brain MRI pattern consistent with Leigh syndrome. Here, we report three patients belonging to a consanguineous family who presented with mitochondrial encephalomyopathy. Whole-exome sequencing revealed a new homozygous mutation c.619G > A (p.Gly207Ser) at the last nucleotide position in exon 5 of the ECHS1 gene. Experimental analysis showed that normal ECHS1 pre-mRNA splicing occurred in all patients compared to controls. Furthermore, three-dimensional models of wild-type and mutant echs1 proteins revealed changes in catalytic site interactions, conformational changes, and intramolecular interactions, potentially disrupting echs1 protein trimerization and affecting its function. Additionally, the quantification of mtDNA copy number variation in blood leukocytes showed severe mtDNA depletion in all probands.
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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We thank all the members of the family for their cooperation in the present study.
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This work was supported by The Ministry of Higher Education and Scientifc Research in Tunisia and the University of Sharjah,UAE.
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MM: Elaborating the manuscript and conducting experimental analysis and interpretation of clinical, molecular, genetic, and in silico data. TK and LS: gathering, evaluating, and interpreting clinical data. Molecular and bioinformatics data analysis: OA, BK, MA, and RF. Overseeing the molecular genetic analyses are AT and CJ. MK: the manuscript has undergone a critical revision for intellectual content. FF: managing the research, collecting genetic information, and editing the manuscript critically for intellectual content. The final manuscript was read and approved by all authors.
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Maalej, M., Sfaihi, L., Fersi, OA. et al. Molecular and in silico investigation of a novel ECHS1 gene mutation in a consanguine family with short-chain enoyl-CoA hydratase deficiency and Mt-DNA depletion: effect on trimer assembly and catalytic activity. Metab Brain Dis 39, 611–623 (2024). https://doi.org/10.1007/s11011-024-01343-6
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DOI: https://doi.org/10.1007/s11011-024-01343-6