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      Lack of Association between Leber’s Hereditary Optic Neuropathy Primary Point Mutations and Multiple Sclerosis in Iran

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          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 polymerase chain reaction and restriction fragment length polymorphism. Our results suggest that there is no association between Iranian patients with MS and mtDNA point mutations at np 11,778, 3,460, and 14,484.

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          Most cited references 10

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          Oxygen activation and the conservation of energy in cell respiration.

          Many of the membrane-associated oxidases that catalyse respiratory reduction of O2 to water simultaneously couple this exergonic reaction to the translocation of protons across the inner mitochondrial membrane, or the cell membrane in prokaryotes, a process by which metabolic energy is conserved for subsequent synthesis of ATP. The molecular mechanism of O2 reduction and its linkage to H+ translocation are now emerging. The bimetallic haem iron-copper reaction centre in this family of enzymes is the critical structure for catalysis of both these processes.
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            SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome.

            Leigh Syndrome (LS) is a severe neurological disorder characterized by bilaterally symmetrical necrotic lesions in subcortical brain regions that is commonly associated with systemic cytochrome c oxidase (COX) deficiency. COX deficiency is an autosomal recessive trait and most patients belong to a single genetic complementation group. DNA sequence analysis of the genes encoding the structural subunits of the COX complex has failed to identify a pathogenic mutation. Using microcell-mediated chromosome transfer, we mapped the gene defect in this disorder to chromosome 9q34 by complementation of the respiratory chain deficiency in patient fibroblasts. Analysis of a candidate gene (SURF1) of unknown function revealed several mutations, all of which predict a truncated protein. These data suggest a role for SURF1 in the biogenesis of the COX complex and define a new class of gene defects causing human neurodegenerative disease.
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              Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.

              Leigh disease associated with cytochrome c oxidase deficiency (LD[COX-]) is one of the most common disorders of the mitochondrial respiratory chain, in infancy and childhood. No mutations in any of the genes encoding the COX-protein subunits have been identified in LD(COX-) patients. Using complementation assays based on the fusion of LD(COX-) cell lines with several rodent/human rho0 hybrids, we demonstrated that the COX phenotype was rescued by the presence of a normal human chromosome 9. Linkage analysis restricted the disease locus to the subtelomeric region of chromosome 9q, within the 7-cM interval between markers D9S1847 and D9S1826. Candidate genes within this region include SURF-1, the yeast homologue (SHY-1) of which encodes a mitochondrial protein necessary for the maintenance of COX activity and respiration. Sequence analysis of SURF-1 revealed mutations in numerous DNA samples from LD(COX-) patients, indicating that this gene is responsible for the major complementation group in this important mitochondrial disorder.

                Author and article information

                Eur Neurol
                European Neurology
                S. Karger AG
                March 2004
                04 March 2004
                : 51
                : 2
                : 68-71
                aNational Research Center for Genetic Engineering and Biotechnology, and bDepartment of Neurology, Tehran University School of Medicine, Shariati Hospital, Tehran, Iran
                75518 Eur Neurol 2004;51:68–71
                © 2004 S. Karger AG, Basel

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                References: 38, Pages: 4
                Original Paper


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