Four novel mutations in the mitochondrial ND4 gene of complex I in patients with multiple sclerosis

Alharbi,Maram  Atallah; Al-Kafaji,Ghada; Khalaf,Noureddine  Ben; Messaoudi,Safia  Abdulsalam; Taha,Safa; Daif,Abdulqader; Bakhiet,Moiz

doi:10.3892/br.2019.1250

Four novel mutations in the mitochondrial ND4 gene of complex I in patients with multiple sclerosis

Authors:
- Maram Atallah Alharbi
- Ghada Al-Kafaji
- Noureddine Ben Khalaf
- Safia Abdulsalam Messaoudi
- Safa Taha
- Abdulqader Daif
- Moiz Bakhiet
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Affiliations: College of Forensic Sciences, Naif Arab University for Security Sciences, Riyadh 14812, Kingdom of Saudi Arabia, Department of Molecular Medicine, Al-Jawhara Centre for Genetics and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Block 329, Manama, Kingdom of Bahrain, Department of Life Sciences, College of Graduate Studies, Arabian Gulf University, Block 329, Manama, Kingdom of Bahrain, King Saud University Medical City, Riyadh 12372, Kingdom of Saudi Arabia
Published online on: November 4, 2019 https://doi.org/10.3892/br.2019.1250
Pages: 257-268
Copyright: © Alharbi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Multiple sclerosis (MS) is an immune-mediated neurological, inflammatory disease of the central nervous system. Recent studies have suggested that genetic variants in mitochondrial DNA (mtDNA)‑encoded complexes of respiratory chain, particularly, complex I (NADH dehydrogenase), contribute to the pathogenicity of MS among different ethnicities, and targeting mitochondrial function may represent a novel approach for MS therapy. In this study, we sequenced ND genes (ND1, ND2, ND3, ND4, ND4L, ND5 and ND6) encoding subunits of complex I in 124 subjects, 60 patients with relapsing-remitting MS and 64 healthy individuals, in order to identify potential novel mutations in these patients. We found several variants in ND genes in both the patients and controls, and specific variants only in patients with MS. While the majority of these variants were synonymous, 4 variants in the ND4 gene were identified as missense mutations in patients with MS. Of these, m.11150G>A was observed in one patient, whereas m.11519A>C, m.11523A>C and m.11527C>T were observed in another patient. Functional analysis predicted the mutations, m.11519A>C, m.11523A>C and m.11150G>A, as deleterious with a direct impact on ND4 protein stability and complex I function, whereas m.11527C>T mutation had no effect on ND4 protein stability. However, the 3 mutations, m.11519A>C, m.11523A>C and m.11527C>T, which were observed in the same patient, were predicted to cause a cumulative destabilizing effect on ND4 protein, and could thus disrupt complex I function. On the whole, this study identified 4 novel mutations in the mtDNA-encoded ND4 gene in patients with MS, which could lead to complex I dysfunction, and further confirmed the implication of mtDNA mutations in the pathogenicity of MS. The identified novel mutations in patients with MS may be ethnic-related and may prove to be significant in personalized treatment.

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