LHON mutations in Italian patients affected by multiple sclerosis (original) (raw)
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Scientific Reports, 2022
Several mitochondrial DNA (mtDNA) mutations of Leber's hereditary optic neuropathy (LHON) have been reported in patients with multiple sclerosis (MS) from different ethnicities. To further study the involvement of LHON mtDNA mutations in MS in the Arab population, we analyzed sequencing data of the entire mitochondrial genome from 47 unrelated Saudi individuals, 23 patients with relapse-remitting MS (RRMS) and 24 healthy controls. Ten LHON mutations/variants were detected in the patients but were absent in the controls. Of them, the common primary pathogenic mutation m.14484T>C and the rare mutation m.10237T>C were found in one patient, whereas the rare mutation m.9101T>C was found in another patient. The remaining were secondary single nucleotide variants (SNVs) found either in synergy with the primary/rare mutations or individually in other patients. Patients carrying LHON variants also exhibited distinct mtDNA variants throughout the mitochondrial genome, eight were previously reported in patients with LHON. Moreover, five other LHON-related SNVs differed significantly in their prevalence among patients and controls (P < 0.05). This study, the first to investigate LHON mtDNA mutations/variants in a Saudi cohort may suggest a role of these mutations/variants in the pathogenesis or genetic predisposition to MS, a possibility which needs to be explored further in a large-scale. Multiple sclerosis (MS) is a progressive neurological disease characterized by autoimmune inflammation coupled with demyelination and neurodegeneration 1,2. The disease which affects over two million people worldwide, is more common in females than in males 2,3. The exact cause of MS is still unclear, but it is believed that genetic predisposition, epigenetic factors and various environmental factors such as infections, vitamin D deficiency, and smoking contribute significantly to the development of the disease 4,5. These agents are able to trigger a cascade of events in the immune system including an accumulation of macrophages in microglia in the brain and lymphocytes in the white matter and the gray matter of the central nervous system (CNS), leading to demyelination and destruction of axons 6. In recent years, mitochondrial dysfunction has been shown to occur early in MS and plays an important role in the axonal degeneration and demyelination 7-9. Abnormalities in the mitochondrial genome including defects in the mitochondrial DNA (mtDNA), altered mtDNA content and dysregulation of mitochondrial gene expression, which ultimately lead to increase production of free radical and oxidative damage, have all been reported in patients with MS 9,10. The main role of mitochondria is to produce energy through oxidative phosphorylation (OXPHOS). The human mtDNA is a 16.6 kb circular double-stranded DNA molecule which encodes 13 OXPHOS proteins, 22 tRNA genes and 2 rRNA genes. The mtDNA-encoded genes include seven subunits of NADH
Mitochondrial DNA variants in Bulgarian patients affected by multiple sclerosis
European Journal of Neurology, 2007
The occurrence of multiple sclerosis (MS) in subjects clustering to a particular mitochondrial DNA (mtDNA) haplogroup/haplotype or carrying mtDNA mutations associated with Leber's hereditary optic neuropathy (LHON) has suggested that mitochondrial genome may contribute to susceptibility to MS. In the present study, 58 unrelated Bulgarian patients with relapsing remitting form of MS and 104 randomly selected healthy individuals were analysed for the presence of 14 mtDNA polymorphisms determining major European haplogroups as well as three (4216, 14 798, 13 708) secondary LHON mutations. Restriction enzyme analysis used to screen patients and controls for the common haplogroup-associated polymorphisms showed that each of these changes was present in MS patients at a similar frequency to control subjects. However, 21 of the 58 patients (36.2%) were positive for T4 216C mutation, while only 11.3% of the controls carried this secondary LHON base change (P < 0.01; OR ¼ 4.38). Our finding indicated that 4216C base substitution could be considered as a predisposing marker for MS and supported the hypothesis that particular mtDNA variants could contribute to genetic susceptibility of MS, and merits further investigation.
European Neurology, 2004
The hypothesis that mitochondrial genes may implicate susceptibility to multiple sclerosis (MS) is supported by an increasing number of case reports on Leber’s hereditary optic neuropathy (LHON)-associated mitochondrial DNA (mtDNA) point mutations in patients with MS. A number of mtDNA mutations with primary pathogenic significance for LHON, a maternally inherited disease causing severe bilateral visual loss predominantly in young men, have been detected in patients with an MS-like phenotype. To evaluate the link between MS and LHON primary point mutations, we investigated 31 non-related Iranian clinically definite MS patients (23 females and 8 males) with optic nerve involvement, as well as 25 patients (16 females and 9 males) without involvement of the optic nerve as controls. Three patients had severe bilateral visual loss without any recovery. We searched for the presence of LHON mitochondrial mutations at nucleotide positions (np) 11,778, 3,460, and 14,484 by mutation-specific ...
Multiple sclerosis and mitochondrial gene variations: A review
Journal of the Neurological Sciences, 2013
Multiple sclerosis (MS) is a debilitating disease of the central nervous system. Its etiology is still an unanswered enigma; its symptoms are varied and unpredictable; and there is no cure for it. Genetics has been introduced as a contributing factor to MS. Not only may MS stem from nuclear gene variations/mutations, but also it may arise from mitochondrial gene variations/mutations. The association of mitochondrial DNA variations/mutations with the pathogenesis of MS has, so far, been analyzed by several studies. This paper reviews the literature with regard to MS and corresponding mitochondrial DNA variations.
Cellular and molecular …, 2006
As multiple sclerosis (MS) has long been known to be associated with Leber, hereditary optic neuropathy (LHON), a disease caused by mitochondrial (mtDNA) mutations, in this study we assessed possible involvement of mtDNA point mutation in MS patients. Fifty-two MS patients whose disease was confirmed with revised McDonald criteria and referred to Iranian Center of Neurological Research of Imam Khomeini hospital during 2006-2007 entered the study. Secondary mtDNA mutations, age, gender, clinical disability according to expanded disability status scale (EDSS), course of the disease, and presenting symptoms were the variables investigated in this study. DNA purification was performed by Diatom DNA Extraction Kit. Analysis of data was done by SPSS V11.5. The prevalent mutations with frequency of 19.2% were J, L, and T haplogroups. Haplotype A was more prevalent in patients with younger age of onset (P-value = 0.012) and high proportion of haplogroup H was associated with optic nerve involvement (P-value = 0.015). No motor symptoms were seen in haplogroup H patients. There is no significant relationship between duration of the disease and EDSS in different mutation of mtDNA.