Dataset Information

Leber's Hereditary Optic Neuropathy-Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family.

ABSTRACT: Purpose:Leber's hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA)-associated, maternally inherited eye disease. Mutation heteroplasmy level is one of the leading causes to trigger LHON manifestation. In this study, we aimed to identify the causative mutation in a large Han Chinese family with LHON and explore the underlying pathogenic mechanism in this LHON family. Methods:The whole-mtDNA sequence was amplified by long-range PCR. Mutations were subsequently identified by next-generation sequencing (NGS) and validated by Sanger sequencing. The heteroplasmy rates of those family members were determined by digital PCR (dPCR). Mitochondrial haplogroups were assigned based on mtDNA tree build 17. Results:The m.14495A>G mutation was identified as causative due to its higher heteroplasmy level (>50%) in patients than in their unaffected relatives. All mutation carriers belong to M7b1a1 and are assigned to Asian mtDNA lineage. Interestingly, our result revealed that high mtDNA copy number in carrier might prevent LHON manifestation. Conclusions:This is the first report of m.14495A>G mutation in Asian individuals with LHON. Our study shows that dPCR technology can provide more reliable results in mutation heteroplasmy assay and determination of the cellular mtDNA content, making it a potentially promising tool for clinical precise diagnosis of LHON. Furthermore, our results also add evidence to the opinion that higher mtDNA content may protect mutation carriers from LHON. Translational Relevance:dPCR can be used for the assessment of LHON disease, and a new genetic-based diagnostic strategy has been proposed for LHON patients with the m.14495A>G mutation.

SUBMITTER: Li S

PROVIDER: S-EPMC6615366 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Leber's Hereditary Optic Neuropathy-Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family.

Li Shouqing S Duan Shan S Qin Yueyuan Y Lin Sheng S Zheng Kaifeng K Li Xi X Zhang Linghua L Gu Xueying X Yao Keqin K Wang Baojiang B

Translational vision science & technology 20190703 4

<h4>Purpose</h4>Leber's hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA)-associated, maternally inherited eye disease. Mutation heteroplasmy level is one of the leading causes to trigger LHON manifestation. In this study, we aimed to identify the causative mutation in a large Han Chinese family with LHON and explore the underlying pathogenic mechanism in this LHON family.<h4>Methods</h4>The whole-mtDNA sequence was amplified by long-range PCR. Mutations were subsequently identif ...[more]

PMID: 31316863

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Project description:PurposeTo investigate the role of mitochondrial haplotypes in the development of Leber's hereditary optic neuropathy (LHON) associated with the ND4 G11778A mutation in Chinese families.DesignEight Han Chinese families with maternally transmitted LHON were studied using clinical, genetic, and molecular evaluations.ParticipantsOne hundred sixty-seven subjects from 8 Chinese families with a wide age range and severity of visual impairment.MethodsAll subjects underwent the clinical and genetic evaluation, as well as molecular analysis of mitochondrial DNA (mtDNA).Main outcome measuresThe ophthalmologic examinations included visual acuity, visual field examination, visual evoked potentials, and fundus photography. Mitochondrial DNA analysis included the polymerase chain reaction amplification of the entire mtDNA and subsequent sequence determination.ResultsEight families exhibited extremely low penetrance of visual impairment, with the average of 13%. In particular, 14 (12 males and 2 females) of 119 matrilineal relatives in these families exhibited the variable severity and age at onset in visual dysfunction. The average age of onset of vision loss was 17 years. Molecular analysis of mtDNA identified the homoplasimic ND4 G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M8a2, D4g2, B4a1c, B5b, N9a1, D4b2b, C, and M7b1. However, there was an absence of secondary LHON-associated mtDNA mutations in these 8 Chinese families.ConclusionsThe extremely low penetrance of vision loss in these 8 Chinese pedigrees strongly indicates that the G11778A mutation was itself insufficient to produce a clinical phenotype. The absence of secondary LHON mtDNA mutations suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the G11778A mutation in those Chinese families with very low penentrace of vision loss. However, nuclear backgrounds and environmental factors seem to be modifying factors for the phenotypic manifestation of the G11778A mutation in these Chinese families.

Dataset Information

Leber's Hereditary Optic Neuropathy-Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family.

Publications

Leber's Hereditary Optic Neuropathy-Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family.

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