Prevalence of Mitochondrial<i>ND4</i>Mutations in 1281 Han Chinese Subjects With Leber's Hereditary Optic Neuropathy

Jiang, Pingping; Liang, Min; Zhang, Juanjuan; Gao, Yinglong; He, Zheyun; Yu, Han; Zhao, Fuxin; Ji, Yanchun; Liu, Xiaoling; Zhang, Minglian; Fu, Qun; Tong, Yi; Sun, Yanhong; Zhou, Xiangtian; Huang, Taosheng; Qu, Jia; Guan, Min‐Xin

doi:10.1167/iovs.14-16158

Cited by 50 publications

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“…Mutations of the multi-gene panel were designed from the Mitomap database, previous reports and our previous study in a Chinese Han population (8)(9)(10). Twenty-seven amplicons, the specific primers for the point mutations, covered those of 46 mutations, as well as other substitutions in the amplicons, such as pathogenic mutations, m.3697G>A, m.10197G>A and m.14459G>A in the fragments of amplicon 4, 13 and 23, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…A total of 275 unrelated LHON samples and 281 Chinese control samples were enrolled from the ophthalmology clinics at Zhejiang University School of Medicine (Hangzhou, China) and Wenzhou Medical College (Wenzhou, China) between 2004 and 2015, as described previously (8)(9)(10)12), under protocols approved by Zhejiang University and Wenzhou Medical University Ethics Committees. DNA was extracted from 1 ml peripheral blood using a QIAamp DNA Blood Minikit (51106; Qiagen China Co., Ltd., Shanghai, China).…”

Section: Dna Samples Extraction Quantification and Quality Controlmentioning

confidence: 99%

“…Multi-gene target sequencing was performed using the VariantPro™ Capture Technology by LC Sciences (Hangzhou, China) as described previously (13). The 46 LHON-associated mutations were selected from Mitomap and previous studies (8)(9)(10). As presented in Table I, they Library preparation and sequencing.…”

Section: Dna Samples Extraction Quantification and Quality Controlmentioning

confidence: 99%

“…The three most causative mutations, m.11778G>A (M T-ND4), m.14484T>C (M T-ND6) and m.3460G>A (MT-ND1), have been reported to account for 90% of LHON patients in a Caucasian population, but for only 38.3 and 46.5% of cases in two large cohorts of Chinese Han subjects with LHON (7)(8)(9)(10). Our previous studies have shown the spectrum of genes, MT-ND1, MT-ND4 and MT-ND6, and the frequency of the three primary mutations in a Chinese LHON population (8-10) using Sanger sequencing.…”

Section: Introductionmentioning

confidence: 99%

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Mutation analysis of Leber's hereditary optic neuropathy using a multi‑gene panel

et al. 2017

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Abstract. The present study investigates the spectrum and incidence of mitochondrial DNA (mtDNA) mutations associated with Leber's hereditary optic neuropathy (LHON) in a Han population using a multi-gene panel with 46 LHON-associated mutations among 13 mitochondrial genes. A total of 23 mutations were observed in a cohort of 275 patients and 281 control subjects using multi-gene panel analysis IntroductionLeber's hereditary optic neuropathy (LHON; OMIM 535000) is a classic mitochondrial disease, associated with a rapid, painless, acute or sub-acute bilateral visual loss in young adults, predominantly caused by the primary and secondary mutations in mitochondrial DNA (mtDNA). It has been reported that 1:8,500 individuals harbor a primary LHON-causing mutation and 1:31,000 experience visual loss as a result of LHON in the North East of England (1). Few significant improvements in visual acuity are reported following atrophy of the optic discs. LHON typically affects males more frequently than females, with the incomplete and variable penetrance estimated at ~50% in males and 10% in females (2-4). Additionally, certain LHON cases have additional clinical symptoms, such as movement disorders, dystonia, and multiple-sclerosis-like illness, which complicate the diagnosis in the clinical setting (5-7). Although the majority ofcases of LHON transmitted by maternal inheritance have a history of visual loss in families, up to 40% of cases are sporadic (5).The genetic cause of LHON is mutations in the mitochondrial genome, which is a double-stranded 16,569-nucleotide pair, circular molecule, consisting of one D-Loop region and 37 genes. The three most causative mutations, m.11778G>A (M T-ND4), m.14484T>C (M T-ND6) and m.3460G>A (MT-ND1), have been reported to account for 90% of LHON patients in a Caucasian population, but for only 38.3 and 46.5% of cases in two large cohorts of Chinese Han subjects with LHON (7-10). Our previous studies have shown the spectrum of genes, MT-ND1, MT-ND4 and MT-ND6, and the frequency of the three primary mutations in a Chinese LHON population (8-10) using Sanger sequencing. In addition, secondary mutations that contributed to the high penetrance,

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Section: Discussionmentioning

confidence: 99%

Section: Dna Samples Extraction Quantification and Quality Controlmentioning

confidence: 99%

Section: Dna Samples Extraction Quantification and Quality Controlmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutation analysis of Leber's hereditary optic neuropathy using a multi‑gene panel

et al. 2017

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“…7,19,20 In this cohort, 503 probands had a family history of optic neuropathy, and 778 subjects were sporadic cases. 7 Mutational analysis showed that mutations in MT-ND4 and MT-ND6 genes are responsible for 39.5% and 9.3% cases of LHON subjects in this large cohort, respectively. 7,19 In the present study, we carried out a systematic and extended mutational screening of the MT-ND1 gene in a cohort of 1281 genetically unrelated Han Chinese subjects with LHON.…”

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confidence: 76%

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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Epidemiology of Mitochondrial Disease

Schaefer

Lim

Gorman

2019

Diagnosis and Management of Mitochondrial Disorders

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Prevalence of MitochondrialND4Mutations in 1281 Han Chinese Subjects With Leber's Hereditary Optic Neuropathy

Abstract: These results suggested that the ND4 gene is the hot spot for mutations associated with LHON. Thus, these findings may provide valuable information for the further understanding of pathogenic mechanism of LHON.

Cited by 50 publications

References 59 publications

Mutation analysis of Leber's hereditary optic neuropathy using a multi‑gene panel

Mutation analysis of Leber's hereditary optic neuropathy using a multi‑gene panel

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

Epidemiology of Mitochondrial Disease

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