Sequence analysis of Hungarian LHON patients not carrying the common primary mutations (original) (raw)
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Mitochondrial genome variation in male LHON patients with the m.11778G > A mutation
Metabolic Brain Disease
Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with symptoms limited to a single tissue, optic nerve, resulting in vision loss. In the majority of cases it is caused by one of three point mutations in mitochondrial DNA (mtDNA) but their presence is not sufficient for disease development, since ~50% of men and ~10% women who carry them are affected. Thus additional modifying factors must exist. In this study, we use next generation sequencing to investigate the role of whole mtDNA variation in male Polish patients with LHON and m.11778G > A, the most frequent LHON mutation. We present a possible association between mtDNA haplogroup K and variants in its background, a combination of m.3480A > G, m.9055G > A, m.11299 T > C and m.14167C > T, and LHON mutation. These variants may have a negative effect on m.11778G > A increasing its penetrance and the risk of LHON in the Polish population. Surprisingly, we did not observe associations previously re...
… and biophysical research …, 2007
For identifying mutation(s) that are potentially pathogenic it is essential to determine the entire mitochondrial DNA (mtDNA) sequences from patients suffering from a particular mitochondrial disease, such as Leber hereditary optic neuropathy (LHON). However, such sequencing efforts can, in the worst case, be riddled with errors by imposing phantom mutations or misreporting variant nucleotides, and moreover, by inadvertently regarding some mutations as novel and pathogenic, which are actually known to define minor haplogroups. Under such circumstances it remains unclear whether the disease-associated mutations would have been determined adequately. Here, we re-analyse four problematic LHON studies and propose guidelines by which some of the pitfalls could be avoided.
Mitochondrial DNA Haplogroup Background Affects LHON, but Not Suspected LHON, in Chinese Patients
PLoS ONE, 2011
Recent studies have shown that mtDNA background could affect the clinical expression of Leber hereditary optic neuropathy (LHON). We analyzed the mitochondrial DNA (mtDNA) variation of 304 Chinese patients with m.11778G.A (sample #1) and of 843 suspected LHON patients who lack the three primary mutations (sample #2) to discern mtDNA haplogroup effect on disease onset. Haplogroup frequencies in the patient group was compared to frequencies in the general Han Chinese population (n = 1,689; sample #3). The overall matrilineal composition of the suspected LHON population resembles that of the general Han Chinese population, suggesting no association with mtDNA haplogroup. In contrast, analysis of these LHON patients confirms mtDNA haplogroup effect on LHON. Specifically, the LHON sample significantly differs from the general Han Chinese and suspected LHON populations by harboring an extremely lower frequency of haplogroup R9, in particular of its main sub-haplogroup F (#1 vs. #3, P-value = 1.46610 217 , OR = 0.051, 95% CI: 0.016-0.162; #1 vs. #2, P-value = 4.44610 217 , OR = 0.049, 95% CI: 0.015-0.154; in both cases, adjusted P-value ,10 25) and higher frequencies of M7b (#1 vs. #3, adjusted P-value = 0.001 and #1 vs. #2, adjusted P-value = 0.004). Our result shows that mtDNA background affects LHON in Chinese patients with m.11778G.A but not suspected LHON. Haplogroup F has a protective effect against LHON, while M7b is a risk factor.
PLoS ONE, 2010
Background: Leber hereditary optic neuropathy (LHON, MIM 535000) is one of the most common mitochondrial genetic disorders caused by three primary mtDNA mutations (m.3460G.A, m.11778G.A and m. 14484T.C). The clinical expression of LHON is affected by many additional factors, e.g. mtDNA background, nuclear genes, and environmental factors. Hitherto, there is no comprehensive study of Chinese LHON patients with m.14484T.C. Methodology/Principal Findings: In this study, we analyzed the mtDNA sequence variations and haplogroup distribution pattern of the largest number of Chinese LHON patients with m.14484T.C to date. We first determined the complete mtDNA sequences in eleven LHON probands with m.14484T.C, to discern the potentially pathogenic mutations that cosegregate with m.14484T.C. We then dissected the matrilineal structure of 52 patients with m.14484T.C (including 14 from unrelated families and 38 sporadic cases) and compared it with the reported Han Chinese from general populations. Complete mtDNA sequencing showed that the eleven matrilines belonged to nine haplogroups including Y2,
Mitochondrial DNA copy number in affected and unaffected LHON mutation carriers
BMC Research Notes, 2018
Objectives: Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease characterized by a variable and reduced penetrance. Individuals carrying a primary LHON-causing mitochondrial DNA (mtDNA) mutation may either remain asymptomatic lifelong, as unaffected carriers, or develop sudden central visual loss that rapidly aggravates over some weeks. Over the years several genetic/environmental triggers able to modulate the risk of developing LHON have been proposed. We provided data supporting a possible correlation between LHON pen-etrance and the mtDNA copy number, a raw index of mitochondrial mass, whose increase could represent a compensatory response that cells implement to alleviate the pathogenic effect of the primary LHON-causing mtDNA mutations. Data description: We collected Italian and Spanish subjects harboring one of the three common LHON primary mutations, either in heteroplasmic or homoplasmic status. For each population we were able to discriminate between affected subjects presenting typical clinical tracts of LHON and LHON-causing mutation carriers showing no symptoms correlated with vision loss. Each subject has been characterized for the presence of a LHON primary mutation, for its status of homoplasmy or heteroplasmy, and for the mtDNA content per cell, expressed as relative mtDNA/ nDNA ratio respect to controls. Additional clinical information is present for all the Italian subjects.
PloS one, 2016
The presence of more than one non-severe pathogenic mutation in the same mitochondrial DNA (mtDNA) molecule is very rare. Moreover, it is unclear whether their co-occurrence results in an additive impact on mitochondrial function relative to single mutation effects. Here we describe the first example of a mtDNA molecule harboring three Leber's hereditary optic neuropathy (LHON)-associated mutations (m.11778G>A, m.14484T>C, m.11253T>C) and the analysis of its genetic, biochemical and molecular characterization in transmitochondrial cells (cybrids). Extensive characterization of cybrid cell lines harboring either the 3 mutations or the single classic…
Human Genetics, 2002
Leber's hereditary optic neuropathy (LHON) is a maternally transmitted form of blindness caused by mitochondrial DNA (mtDNA) mutations. Approximately 90% of LHON cases are caused by 3460A, 11778A, or 14484C mtDNA mutations. These are designated "primary" mutations because they impart a high risk for LHON expression. Although the 11778A and 14484C mutations unequivocally predispose carriers to LHON, they are preferentially associated with mtDNA haplogroup J, one of nine Western Eurasian mtDNA lineages, suggesting a synergistic and deleterious interaction between these LHON mutations and haplogroup J polymorphism(s). We report here the characterization of a new primary LHON mutation in the mtDNA ND4L gene at nucleotide pair 10663. The homoplasmic 10663C mutation has been found in three independent LHON patients who lack a known primary mutation and all of which belong to haplogroup J. This mutation has not been found in a large number of haplotype-matched or non-haplogroup-J control mtDNAs. Phylogenetic analysis with primarily complete mtDNA sequence data demonstrates that the 10663C mutation has arisen at least three independent times in haplogroup J, indicating that it is not a rare lineage-specific polymorphism. Analysis of complex I function in patient lymphoblasts and transmitochondrial cybrids has revealed a partial complex I defect similar in magnitude to the 14484C mutation. Thus, the 10663C mutation appears to be a new primary LHON mutation that is pathogenic when co-occurring with hap-logroup J. These results strongly support a role for haplogroup J in the expression of certain LHON mutations.
PLoS ONE, 2011
Mitochondrial transfer RNA (mt-tRNA) mutations have been reported to be associated with a variety of diseases. In a previous paper that studied the mtDNA background effect on clinical expression of Leber's hereditary optic neuropathy (LHON) in 182 Chinese families with m.11778G.A, we found a strikingly high frequency (7/182) of m.593T.C in the mitochondrially encoded tRNA phenylalanine (MT-TF) gene in unrelated LHON patients. To determine the potential role of m.593T.C in LHON, we compared the frequency of this variant in 479 LHON patients with m.11778G.A, 843 patients with clinical features of LHON but without the three known primary mutations, and 2374 Han Chinese from the general populations. The frequency of m.593T.C was higher in LHON patients (14/479) than in suspected LHON subjects (12/843) or in general controls (49/2374), but the difference was not statistically significant. The overall penetrance of LHON in families with both m.11778G.A and m.593T.C (44.6%) was also substantially higher than that of families with only m.11778G.A (32.9%) (P = 0.083). Secondary structure prediction of the MT-TF gene with the wild type or m.593T.C showed that this nucleotide change decreases the free energy. Electrophoretic mobility of the MT-TF genes with the wild type or m.593T.C transcribed in vitro further confirmed the change of secondary structure in the presence of this variant. Although our results could suggest a modest synergistic effect of variant m.593T.C on the LHON causing mutation m.11778G.A, the lack of statistical significance probably due to the relatively small sample size analyzed, makes necessary more studies to confirm this effect.