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Complete mitochondrial DNA genome sequence variation of Chinese families with mutation m.3635G>A and Leber hereditary optic neuropathy.

ABSTRACT: PURPOSE: The majority of Leber hereditary optic neuropathy (LHON) cases are caused by one of three mitochondrial DNA (mtDNA) primary mutations (m.3460G>A, m.11778G>A, and m.14484T>C). In recent studies, we and others have shown that mutation m.3635G>A is a primary LHON mutation, particularly in Chinese. The purpose of this study was to perform a thorough analysis for the complete mtDNA genome sequence variation in Chinese patients with m.3635G>A and to identify potentially functional variants cosegregated with m.3635G>A. METHODS: The complete mtDNA genomes of five Chinese patients with LHON carrying m.3635G>A were determined. A phylogenetic tree was constructed to distinguish the private and ancestral mtDNA variants in each lineage. Previously unreported variants in each mtDNA were defined with a web-based and database search. mtDNA variants that changed the structure of the membrane-spanning region of the protein were also evaluated, together with evolutionary conservation analysis, to predict their potential pathogenicity. RESULTS: The five patients with LHON sequenced in this study belonged to haplogroups M7b4 (Le131), F1a (Le329 and Le337), B5b (Le569), and M7b6 (Le834), which suggested multiple origins of m.3635G>A. Private variants m.12811T>C, m.14063T>C, m.15237T>C, and m.9071C>T in these patients were predicted to change the structure of the membrane-spanning region of the respective proteins. CONCLUSIONS: Mutation m.3635G>A had multiple origins in Chinese patients with LHON. We also identified several potentially functional variants cosegregated with m.3635G>A.

SUBMITTER: Bi R

PROVIDER: S-EPMC3538042 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Complete mitochondrial DNA genome sequence variation of Chinese families with mutation m.3635G>A and Leber hereditary optic neuropathy.

Bi Rui R Zhang A-Mei AM Jia Xiaoyun X Zhang Qingjiong Q Yao Yong-Gang YG

Molecular vision 20121230

<h4>Purpose</h4>The majority of Leber hereditary optic neuropathy (LHON) cases are caused by one of three mitochondrial DNA (mtDNA) primary mutations (m.3460G>A, m.11778G>A, and m.14484T>C). In recent studies, we and others have shown that mutation m.3635G>A is a primary LHON mutation, particularly in Chinese. The purpose of this study was to perform a thorough analysis for the complete mtDNA genome sequence variation in Chinese patients with m.3635G>A and to identify potentially functional vari ...[more]

PMID: 23304069

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Project description:PurposeLeber hereditary optic neuropathy (LHON), a maternally inherited disorder, results from point mutations in mitochondrial DNA (mtDNA). MtDNA is highly polymorphic in nature with very high mutation rate, 10-17 fold higher as compared to nuclear genome. Identification of new mtDNA sequence variations is necessary to establish a clean link with human disease. Thus this study was aimed to assess or evaluate LHON patients for novel mtDNA sequence variations.Materials and methodsTwenty LHON patients were selected from the neuro-ophthalmology clinic of the All India Institute of Medical Sciences, New Delhi, India. DNA was isolated from whole blood samples. The entire coding region of the mitochondrial genome was amplified by PCR in 20 patients and 20 controls. For structural analysis (molecular modeling and simulation) the MODELER 9.2 program in Discovery Studio (DS 2.0) was used.ResultsMtDNA sequencing revealed a total of 47 nucleotide variations in the 20 LHON patients and 29 variations in 20 controls. Of 47 changes in patients 21.2% (10/47) were nonsynonymous and the remaining 78.72% (37/47) were synonymous. Five nonsynonymous changes, including primary LHON mutations (NADH dehydrogenase subunit 1 [ND1]:p.A52T, NADH dehydrogenase subunit 6 [ND6]:p.M64V, adenosine triphosphate [ATP] synthase subunit a (F-ATPase protein 6) [ATPase6]:p.M181T, NADH dehydrogenase subunit 4 [ND4]:p.R340H, and cytochrome B [CYB]:p.F181L), were found to be pathogenic. A greater number of changes were present in complex I (53.19%; 25/47), followed by complex III (19.14%; 9/47), then complex IV (19.14%; 9/47), then complex V (8.5%; 4/47). Nonsynonymous variations may impair respiratory chain and oxidative phosphorylation (OXPHOS) pathways, which results in low ATP production and elevated reactive oxygen species (ROS) levels. Oxidative stress is the underlying etiology in various diseases and also plays a crucial role in LHON.ConclusionsThis study describes the role of mtDNA sequence variations in LHON patients. Primary LHON mutations of mtDNA are main variants leading to LHON, but mutations in other mitochondrial genes may also play an important role in pathogenesis of LHON as indicated in the present study. Certain alleles in certain haplogroups have protective or deleterious roles and hence there is a need to analyze a large number of cases for correlating phenotype and disease severity with mutation and mtDNA haplogroups.

Dataset Information

Complete mitochondrial DNA genome sequence variation of Chinese families with mutation m.3635G>A and Leber hereditary optic neuropathy.

Publications

Complete mitochondrial DNA genome sequence variation of Chinese families with mutation m.3635G>A and Leber hereditary optic neuropathy.

Similar Datasets

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