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Molecular characterization of six Chinese families with m.3460G>A and Leber hereditary optic neuropathy

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Abstract

The primary mutation m.3460G>A occurs with a very low frequency (∼1%) in Chinese patients with Leber hereditary optic neuropathy (LHON). Up to now, there is no comprehensive study of Chinese patients harboring this mutation. We characterized six unrelated probands with m.3460G>A in this study, which were identified from 1,626 patients with LHON or suspected with LHON. The overall penetrance of LHON (25.6% [10/39]) in four pedigrees with m.3460G>A was substantially lower than those families with m.11778G>A (33.3% [619/1859]) as reported in our previous study. Intriguingly, family Le688 with a heteroplasmic m.3460G>A presented a lower penetrance (12.5%) than the other three families with a homoplasmic mutation. There is an elevated gender bias (affected male to affected female = 4:1) in the four families with m.3460G>A compared to those LHON families with m.11778G>A (2.4:1). Complete mtDNA sequencing indicated that the six matrilines belonged to haplogroups B4d1, F2, A5b, M12a, D4b2b, and D4b2, respectively. We did not identify any potential secondary mutation(s) that will affect or be associated with the penetrance of LHON in the six probands by using an evolutionary analysis and protein secondary-structure prediction. Taken together, our results suggested that the m.3460G>A mutation occurred multiple times in Chinese LHON patients. The heteroplasmic status of mutation m.3460G>A might influence the penetrance of LHON in family Le688.

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Acknowledgments

We thank patients for participating in this study. We are grateful to the members in Yao’s laboratory for helpful discussions. This study was supported by Yunnan Province (云南省高端人才计划2009CI119), Guangdong Province (广东省中国科学院全面战略合作项目2009B091300150), Chinese Academy of Sciences, and the National Science Fund for Distinguished Young Scholars (30925021).

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Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China

    Dandan Yu, A-Mei Zhang & Yong-Gang Yao

  2. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China

    Xiaoyun Jia, Xiangming Guo & Qingjiong Zhang

  3. State Key Laboratory of Genetic Resource and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China

    Ya-Ping Zhang

  4. Graduate School of the Chinese Academy of Sciences, Beijing, 100039, China

    A-Mei Zhang

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  1. Dandan Yu
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  2. Xiaoyun Jia
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  3. A-Mei Zhang
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  4. Xiangming Guo
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  5. Ya-Ping Zhang
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  7. Yong-Gang Yao
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Correspondence to Qingjiong Zhang or Yong-Gang Yao.

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Fig. S1

Evolutionary conservation analysis of the amino acid change caused by the previously unreported non-synonymous variant m.9423C>T in family Le1027. The amino acid sequences are compared to that derived from the human reference sequence [Homo sapiens (rCRS), GenBank accession number J01415] and nine different vertebrate species from GenBank: gorilla (Gorilla gorilla, NC_001645), mouse (Mus musculus, AY466499), cattle (Bos taurus, AY526085), horse (Equus caballus, EF597513), wolf (Canis lupus chanco, EU442884), dog (Canis familiaris, DQ480502), blue whale (Balaenoptera musculu, NC_001601), frog (Rana nigromaculata, AB043889), and zebrafish (Danio rerio, NC_002333) (DOC 30.5 kb)

Fig. S2

A hydrophilicity chart for the MT-CO3 protein predicted by the TMpred program. The hydrophilicity of the MT-CO3 protein harboring the specific amino acid change caused by m.9423C>T was compared to the wild-type protein (rCRS) (DOC 64 kb)

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Yu, D., Jia, X., Zhang, AM. et al. Molecular characterization of six Chinese families with m.3460G>A and Leber hereditary optic neuropathy. Neurogenetics 11, 349–356 (2010). https://doi.org/10.1007/s10048-010-0236-7

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