Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family

Qu, Jia; Li, Ronghua; Zhou, Xiangtian; Tong, Yi; Yang, Li; Chen, Jie; Zhao, Fuhua; Lu, Chunjie; Qian, Yaping; Liu, Fan; Guan, Min‐Xin

doi:10.1016/j.mito.2006.11.015

Cited by 48 publications

(52 citation statements)

References 29 publications

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“…This panel screening demonstrated that the secondary mutations, m.12811T>C, m.11696G>A, m.3394T>C, m.3316G>A, m.14502T>C and m.12338T>C had higher frequencies in the patient cohort, as these mutations were assigned to Asian mtDNA lineage, including the macro-haplo group of M and N. Certainly, m.12811T>C is considered to be a polymorphic variant in sub-haplo groups of M7. While, mutations, m.3394T>C and m.11696G>A are categorized as haplo group-specific variants of M9a and D4j, respectively (25,26). Congruent results were obtained in our previous reports (27).…”

Section: Discussionmentioning

confidence: 79%

“…Usually, secondary mutations, proposed to increase the penetrance of LHON (25)(26)(27), are observed in LHON cases associated with m.11778G>A or m.14484T>C mutations. In the present study, 77.27% of variations of secondary mutations were coexistent with one of the primary mutations, m.11778G>A and m.14484T>C. Their detailed distribution was illustrated in Table V Table IV.…”

Section: Discussionmentioning

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: 79%

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Of these mtDNA variants, the V313I (G11696A) mutation in ND4 was first identified in a large Dutch family [35] and subsequently in five Chinese pedigrees [36] and coexisted with ND4 G11778A mutation in a Chinese family with higher penetrance of vision loss [37]. However, the extremely low penetrance of visual loss, and the mild biochemical defect [35] and the presence of one/167 Chinese controls indicted that the G11696A mutation is itself not sufficient to produce a clinical phenotype [36].…”

Section: Discussionmentioning

confidence: 99%

“…However, the G-to-A transition at position 11696 (G11696A) in ND4, caused the substitution of an isoleucine for valine at amino acid position 313, as shown in Figure 3, has been found in those subjects. Indeed, this mutation has been associated with LHON and hereditary spastic dystonia in a large Dutch family [35] and LHON in Chinese families [36][37].…”

Section: Mitochondrial Genome Analysismentioning

confidence: 99%

The ND4 G11696A mutation may influence the phenotypic manifestation of the deafness-associated 12S rRNA A1555G mutation in a four-generation Chinese family

Liao¹,

Zhao²,

Zhu³

et al. 2007

Biochemical and Biophysical Research Communications

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We report here the clinical, genetic and molecular characterization of a large Han Chinese family with aminoglycoside induced and nonsyndromic hearing loss. The penetrance of hearing loss (affected matrilineal relatives/total matrilineal relatives) in this pedigree was 53%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrance of hearing loss in this pedigree was 42%. These matrilineal relatives exhibited a wide range of severity of hearing loss, varying from profound to normal hearing. Furthermore, these affected matrilineal relatives shared some common features: bilateral hearing loss of high frequencies and symmetries. Sequence analysis of mitochondrial DNA (mtDNA) in the pedigree identified the homoplasmic 12S rRNA A1555G mutation and other 35 variants belonging to Eastern Asian haplogroup D4. Of these, the V313I (G11696A) mutation in ND4 was associated with vision loss. However, the extremely low penetrance of visual loss, and the mild biochemical defect and the presence of one/167 Chinese controls indicted that the G11696A mutation is itself not sufficient to produce a clinical phenotype. Thus, the G11696A mutation may act in synergy with the primary deafness-associated 12S rRNA A1555G mutation in this Chinese family, thereby increasing the penetrance and expressivity of hearing loss in this Chinese pedigree.

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“…This provides additional evidence that the m.3394T>C mutation is itself not sufficient to produce the clinical phenotype, but triggers, acting as a mitochondrial modifier, the optic neuropathy in subjects harboring m.11778G>A or m.14484T>C mutations, as in the cases of m.14502T>C or m.11696G>A mutations. 7,19,44 Prevalence and Pathogenicity of Other Putative LHON-Associated MT-ND1 MutationsIn the present study, we identified 15 putative LHONassociated mtDNA mutations occurring in 27 probands. In contrast with the m.11778G>A mutation, these mutations appeared at very low frequency in the Chinese cohort.…”

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confidence: 92%

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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Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family

Cited by 48 publications

References 29 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

The ND4 G11696A mutation may influence the phenotypic manifestation of the deafness-associated 12S rRNA A1555G mutation in a four-generation Chinese family

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

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