G6036A substitution in mitochondrial COX I gene compromises cytochrome c oxidase activity in thiamine responsive Leigh syndrome patients
| Autor: | M.V. Kranthi Kumar, S. Narasimha Rao, Shalini Mani |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
In silico
Mutation Missense Biology Genome Electron Transport Complex IV Mitochondrial Proteins 03 medical and health sciences 0302 clinical medicine Missense mutation Cytochrome c oxidase Humans Nucleotide 030212 general & internal medicine Thiamine Gene Genetics chemistry.chemical_classification Genetic heterogeneity Neurology chemistry Mutation biology.protein Cyclooxygenase 1 Neurology (clinical) Leigh Disease 030217 neurology & neurosurgery |
| Zdroj: | Journal of the neurological sciences. 415 |
| ISSN: | 1878-5883 |
| Popis: | Cytochrome c oxidase (COX) deficiency is known to be associated with Leigh syndrome (LS), however there are limited studies on genetic screening of mitochondrial (mt) DNA encoding COX genes as well as the functional validation of identified variants. In our previous studies, we cared for total 165 LS patients and analyzed the nucleotide variations across entire mt genome. We observed a high level of genetic heterogeneity in these patients. We identified various reported and novel variation across entire genome including COX genes. In our present study we have further studied and functionally validated the selected novel nucleotide variant of COX I and COX II gene using different in-silico tools and trans mitochondrial cybrid based assays. As a result of our study, G6036A (G45S) variant of COX I gene, reduced the COX activity in both spectrophotometric as well as In-gel BN-PAGE assays. FACS analysis also revealed this variant to affect the mitochondrial membrane potential in the respective cybrids. Interestingly most of our in-silico studies indicated that this variant might affect the secondary structure and confirmation of COX I protein. Thus we report the first missense mutation in the COX I gene of LS patients and justify its pathogenic role in these patients by different assays. Variant A7746G (N54K) in COX II gene was also predicted to affect the secondary structure as well as stability of COX II protein. Though, the effect of this variant was not significant, however it will be interesting to investigate its significance by other assays in future. |
| Databáze: | OpenAIRE |
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