Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy.

Abstract

Four new missense mutations have been identified through restriction analysis and sequencing of the mitochondrial DNAs (mtDNA) from Leber's hereditary optic neuropathy (LHON) patients who lacked the previously identified 11778 mutation. Each altered a conserved amino acid and correlated with the LHON phenotype in population and phylogenetic analyses. The nucleotide pair (np) 13708 mutation (G to A, ND5 gene) changed an alanine to a threonine and was found in 6/25 (24%) of non-11778 LHON pedigrees and in 5.0% of controls, the np 15257 mutation (G to A, cytochrome b gene) changed an aspartate to an asparagine and was found in 4 of the 13708-positive pedigrees and 0.3% of controls, the np 15812 mutation (G to A, cytochrome b gene) changed a valine to a methionine and was detected in two of the 15257-positive pedigrees and 0.1% of controls and the np 5244 mutation (G to A, ND2 gene) changed a glycine to a serine and was found in one of the 15812-positive patients and none of 2103 controls. The 15257 mutation altered a highly conserved amino acid in an extramembrane domain of cytochrome b that is associated with the ligation of the low potential b566 heme and the 5244 mutation altered a strongly evolutionarily conserved region of the ND2 polypeptide. The 13708 and 15812 mutations changed moderately conserved amino acids. Haplotype and phylogenetic analysis of the four np 15257 mtDNAs revealed that all harbored the same rare Caucasian haplotype and that the np 13708, np 15257, np 15812 and np 5244 mutations were added sequentially along this mtDNA lineage. Since the percentage of sighted controls decreases as these mutations accumulate, it appears that they interact synergistically, each increasing the probability of blindness. The involvement of both mitochondrial complex I (np 5244, 11778, 13708) and complex III (np 15257, 15812) mutations in LHON indicates that the clinical manifestations of this disease are the product of an overall decrease in mitochondrial energy production rather than a defect in a specific mitochondrial enzyme.

How clonal are human mitochondria?

“…We collected 29 largely complete mtDNA sequences from Genbank (human`European', X93334 and humanÀfrican', D38112) and the literature (DCM__P1^FICM (Ozawa et al 1991), BrownI and BrownII (Brown et al 1992a), BrownIII (Brown et al 1992b), TNK203 and TNK205 (Kobayashi et al 1991), Yoneda (Yoneda et al 1990), CMD-1^SVR89-2 (Marzuki et al 1991) and Wallace (Wallace et al 1988)). The`Cambridge' sequence was not included since it is a chimera from two di¡erent individuals (Arnason et al 1996).…”

Mitochondrial Genetic Heterogeneity in Leber’s Hereditary Optic Neuropathy: Original Study with Meta-Analysis

“…After initial screening based on the title and presence of keywords in the articles, a total of 73 articles were reviewed for m.4216T>C and 71 for m.13708G>A. For the final meta-analysis, we included five articles related to m.4216T>C [ 26 , 52 , 63 , 64 , 65 ] and eight articles related to m.13708G>A [ 49 , 61 , 63 , 64 , 65 , 66 , 67 , 68 ]. Other reviewed articles (68 for m.4216T>C and 63 for m.13708G>A) were excluded from the study as a result of (a) the absence of relevant information, (b) lack of relevance of the study to this analysis, (c) lack of control data, or (d) unavailability of full articles.…”

Human Mitochondrial Pathologies of the Respiratory Chain and ATP Synthase: Contributions from Studies of Saccharomyces cerevisiae

“…While some cytochrome b mutations are maternally inherited, others are heteroplasmic and are present mainly in muscle tissue, suggesting that they arise de novo after differentiation of the primary germ layers. Additionally, some LHON patients with a mutation in one of the mitochondrially encoded Complex I genes have a second mutation in cytochrome b, which exacerbates the severity of the pathology [71][72][73]. Mutations in the nuclear UQCR4 (yeast CYC1) and UQCRFS1 (yeast RIP1) genes are much rarer and were more recently identified (Table 3).…”