Mutation Screening of Mitochondrial DNA as Well as OPA1 and OPA3 in a Chinese Cohort With Suspected Hereditary Optic Atrophy

Chen, Jieqiong; Xu, Ke; Zhang, Xiaohui; Jiang, Feng; Liu, Lijuan; Dong, Bing; Ren, Yanfan; Li, Yang

doi:10.1167/iovs.14-14953

Cited by 25 publications

(32 citation statements)

References 40 publications

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“…According to previous studies, the hotspots of OPA1 mutations are distributed in exons, 8, 10, and 27, which code for the GTP domain or putative GED domain [51,52,29,53]. However, we did not detect any OPA1 mutations in exon 2 or exon 10 in the present study.…”

Section: Discussioncontrasting

confidence: 74%

“…The mutational frequency (29.3%) of LHON in this cohort was slightly lower than that of Chinese patients with LHON and any age of onset (38–46%) [29,30]. Among a different cohort in this study, the frequency of the three primary mtDNA mutations (18.9%) in 201 patients with a disease onset age of no more than 10 years (Table 1), was higher than that reported in an Italian study (11.5%) [31].…”

Section: Discussionmentioning

confidence: 93%

“…Recently, many studies analyzed the genes associated with suspected hereditary optic neuropathy in Chinese populations of any age [29,30], however disease onset in childhood was reported as rare. Although DOA commonly initially manifests in patients during childhood while LHON affects juveniles and youths [6,19], an Italian study reported that childhood onset of LHON accounted for 11.5% of cases among pediatric patients with hereditary optic neuropathy onset below 10 years [31].…”

Section: Introductionmentioning

confidence: 99%

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Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy

Jia

et al. 2017

PLoS ONE

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Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA), the most common forms of hereditary optic neuropathy, are easily confused, and it is difficult to distinguish one from the other in the clinic, especially in young children. The present study was designed to survey the mutation spectrum of common pathogenic genes (OPA1, OPA3 and mtDNA genes) and to analyze the genotype-phenotype characteristics of Chinese patients with suspected childhood-onset hereditary optic neuropathy. Genomic DNA and clinical data were collected from 304 unrelated Chinese probands with suspected hereditary optic neuropathy with an age of onset below 14 years. Sanger sequencing was used to screen variants in the coding and adjacent regions of OPA1, OPA3 and the three primary LHON-related mutation sites in mitochondrial DNA (mtDNA) (m.3460G>A, m.11778G>A and m.14484T>C). All patients underwent a complete ophthalmic examination and were compared with age-matched controls. We identified 89/304 (29.3%) primary mtDNA mutations related to LHON in 304 probands, including 76 mutations at m.11778 (76/89, 85.4% of all mtDNA mutations), four at m.3460 (4/89, 4.5%) and nine at m.14484 (9/89, 10.1%). This result was similar to the mutation frequency among Chinese patients with LHON of any age. Screening of OPA1 revealed 23 pathogenic variants, including 11 novel and 12 known pathogenic mutations. This study expanded the OPA1 mutation spectrum, and our results showed that OPA1 mutation is another common cause of childhood-onset hereditary optic neuropathy in Chinese pediatric patients, especially those with disease onset during preschool age.

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Section: Discussioncontrasting

confidence: 74%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy

Jia

et al. 2017

PLoS ONE

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“…9,11,12,36,37 However, the prevalence of the m.3460G>A mutation in the European origins appeared to be higher than that in Asians. Indeed, the incidences of the m.3460G>A mutation varied from 0% to 13% in several European cohorts.…”

Section: Discussion Prevalence and Genetic Features Of The Known Lhonmentioning

confidence: 92%

“…11,12 In particular, the incidences of the m.3460G>A mutation in two large cohorts of Chinese Han subjects with LHON and 159 Caucasian pedigrees with LHON were 0.44%, 2.11%, and 13%, respectively, [10][11][12] suggesting the variable incidence and spectrum of mtDNA mutations among the different ethnic origins. [12][13][14] The other LHON-associated mutations in the MT-ND1 gene included the m.3866T>C, m.3635G>A, and m.3733G>A mutations. [15][16][17] Thus, the MT-ND1 gene is proposed to be another hot spot for mutations associated with LHON.…”

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confidence: 99%

MitochondrialND1Variants in 1281 Chinese Subjects With Leber's Hereditary Optic Neuropathy

Liang

Zhang

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to investigate the mutational incidence and spectrum of mitochondrial ND1 gene in subjects with Leber's hereditary optic neuropathy (LHON). METHODS.A cohort of 1281 Han Chinese probands and 478 control subjects underwent sequence analysis of mitochondrial (mt)DNA. Resultant variants were evaluated for evolutionary conservation, allelic frequencies, and structural and functional consequences. Respiratory complex activities were measured using lymphoblastoid cell lines derived from 25 probands carrying the mtDNA mutation and 3 controls.RESULTS. Mutational analysis identified 178 (70 missense and 108 silent) variants in the MT-ND1 gene. The incidences of known m.3460G>A, m.3635G>A, m.3733G>A, m.3866T>C, and m.3394T>C mutations were 1.33%, 0.86%, 0.08%, 0.55%, and 2.97%, respectively. Fifteen novel putative mutations were identified in 27 probands, translated into 2.1% cases of this cohort. The activity of complex I in mutant cell lines carrying one of putative mutations ranged from 66% to 76% of the average values in control cell lines, whereas activities of complexes II, III, and IV in mutant cells were comparable with those in controls. The low penetrances of optic neuropathy were observed in pedigrees carrying novel putative mutation(s). Moreover, mtDNAs in 101 probands carrying the MT-ND1 mutation(s) were widely dispersed among 15 Eastern Asian haplogroups. In particular, the occurrences of haplogroups M, M9, and M10 in patients carrying the ND1 mutations were higher than those in controls.CONCLUSIONS. These data demonstrated that the MT-ND1 gene is a hot spot for mutations associated with LHON. Our findings may provide valuable information for pathophysiology, management, and genetic counseling of LHON.Keywords: Leber's hereditary optic neuropathy, mitochondrial DNA, mutation, spectrum, ND1 gene L eber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder leading to severe visual impairment or even blindness by death of retinal ganglion cells, affecting children through adults. [1][2][3][4][5] In the majority of cases worldwide, LHON is due to one of three point mutations in the mitochondrial DNA (mtDNA) encoding three subunits of respiratory chain complex I (Nicotinamide adenine dinucleotide [NADH] dehydrogenase): m.3460G>A(MT-ND1), m.11778G>A(MT-ND4), and m.14484T>C(MT-ND6).5-10 These LHON-associated mtDNA mutations occurred in heteroplasmy (mixture of wild-type and mutated molecules) or homoplasmy (only mutated molecules). These three mutations account for approximately 90% of LHON pedigrees in some countries, whereas these mutations are only responsible for 38.3% and 46.5% cases in two large cohorts of Chinese Han subjects with LHON. 11,12 In particular, the incidences of the m.3460G>A mutation in two large cohorts of Chinese Han subjects with LHON and 159 Caucasian pedigrees with LHON were 0.44%, 2.11%, and 13%, respectively, 10-12 suggesting the variable incidence and spectrum of mtDNA mutations among the different ethnic origins.12-14 The ...

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Induced effect of zinc oxide nanoparticles on human acute myeloid leukemia cell apoptosis by regulating mitochondrial division

Yin

Lyu

et al. 2022

IUBMB Life

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Zinc oxide nanoparticles (ZnO NPs) have exhibited excellent anti‐tumor properties; the present study aimed to elucidate the underlying mechanism of ZnO NPs induced apoptosis in acute myeloid leukemia (AML) cells by regulating mitochondrial division. THP‐1 cells, an AML cell line, were first incubated with different concentrations of ZnO NPs for 24 hr. Next, the expression of Drp‐1, Bcl‐2, Bax mRNA, and protein was detected, and the effects of ZnO NPs on the levels of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), apoptosis, and ATP generation in THP‐1 cells were measured. Moreover, the effect of Drp‐1 inhibitor Mdivi‐1 and ZnO NPs on THP‐1 cells was also detected. The results showed that the THP‐1 cells survival rate decreased with the increment of ZnO NPs concentration and incubation time in a dose‐ and time‐dependent manner. ZnO NPs can reduce the cell Δψm and ATP levels, induce ROS production, and increase the levels of mitochondrial division and apoptosis. In contrast, the apoptotic level was significantly reduced after intervention of Drp‐1 inhibitor, suggesting that ZnO NPs can induce the apoptosis of THP‐1 cells by regulating mitochondrial division. Overall, ZnO NPs may provide a new basis and idea for treating human acute myeloid leukemia in clinical practice.

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Mutation Screening of Mitochondrial DNA as Well as OPA1 and OPA3 in a Chinese Cohort With Suspected Hereditary Optic Atrophy

Abstract: The LHON-mtDNA mutations are the most common genetic defects, followed by the OPA1 mutations, in this Chinese cohort.

Cited by 25 publications

References 40 publications

Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy

Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy

MitochondrialND1Variants in 1281 Chinese Subjects With Leber's Hereditary Optic Neuropathy

Induced effect of zinc oxide nanoparticles on human acute myeloid leukemia cell apoptosis by regulating mitochondrial division

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