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The OPA1 Gene Mutations Are Frequent in Han Chinese Patients with Suspected Optic Neuropathy

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Abstract

While many patients with hereditary optic neuropathies are caused by mitochondrial DNA (mtDNA) mutations of Leber’s hereditary optic neuropathy (LHON), a significant proportion of them does not have mtDNA mutation and is caused by mutations in genes of the nuclear genome. In this study, we investigated whether the OPA1 gene, which is a pathogenic gene for autosomal dominant optic atrophy (ADOA), is frequently mutated in these patients. We sequenced all 29 exons of the OPA1 gene in 105 Han Chinese patients with suspected LHON. mtDNA copy number was quantified in blood samples from patients with and without OPA1 mutation and compared to healthy controls. In silico program-affiliated prediction, evolutionary conservation analysis, and in vitro cellular assays were performed to show the potential pathogenicity of the mutations. We identified nine OPA1 mutations in eight patients; six of them are located in exons and three are located in splicing sites. Mutation c.1172T > G has not been reported before. When we combined our data with 193 reported Han Chinese patients with optic neuropathy and compared to the available data of 4327 East Asians by the Exome Aggregation Consortium (ExAC), we found a significant enrichment of potentially pathogenic OPA1 mutations in Chinese patients. Cellular assays for OPA1 mutants c.869G > A and c.2708_2711del showed abnormalities in OPA1 isoforms, mitochondrial morphology, and cellular reactive oxygen species (ROS) level. Our results indicated that screening OPA1 mutation is needed for clinical diagnosis of patients with suspected optic neuropathy.

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Acknowledgments

We thank all participants in this study. We thank Miss Dandan Yu and Dr. Deng-Feng Zhang for the technical assistance. This study was supported by National Natural Science Foundation of China (grant number 81200725) and the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020003).

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Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China

    A-Mei Zhang, Rui Bi, Qiu-Xiang Hu, Yu Fan & Yong-Gang Yao

  2. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China

    A-Mei Zhang

  3. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China

    Qingjiong Zhang

  4. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China

    Yong-Gang Yao

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  1. A-Mei Zhang
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Correspondence to Yong-Gang Yao.

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Written informed consents conforming to the tenets of the Declaration of Helsinki were obtained from each participant prior to the study. The Institutional Review Boards of the Zhongshan Ophthalmic Center and the Kunming Institute of Zoology approved this study.

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Zhang, AM., Bi, R., Hu, QX. et al. The OPA1 Gene Mutations Are Frequent in Han Chinese Patients with Suspected Optic Neuropathy. Mol Neurobiol 54, 1622–1630 (2017). https://doi.org/10.1007/s12035-016-9771-z

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  • DOI: https://doi.org/10.1007/s12035-016-9771-z

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