A novel mutation impairing the tertiary structure and stability of γC-crystallin (CRYGC) leads to cataract formation in humans and zebrafish lens

Authors

  • Xiao-Qiao Li,

    1. Graduate School of Peking Union Medical College, Beijing, China
    2. Department of Genetics, National Research Institute for Family Planning, Beijing, China
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    • These authors contributed equally to the work.

  • Hong-Chen Cai,

    1. State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China
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    • These authors contributed equally to the work.

  • Shi-Yi Zhou,

    1. Graduate School of Peking Union Medical College, Beijing, China
    2. Department of Genetics, National Research Institute for Family Planning, Beijing, China
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    • These authors contributed equally to the work.

  • Ju-Hua Yang,

    1. Biomedical Engineering Center, Fujian Medical University, Fuzhou, Fujian, China
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    • These authors contributed equally to the work.

  • Yi-Bo Xi,

    1. State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China
    2. Institute of Biophysics, Lanzhou University, Lanzhou, China
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    • These authors contributed equally to the work.

  • Xiao-Bo Gao,

    1. Graduate School of Peking Union Medical College, Beijing, China
    2. Department of Genetics, National Research Institute for Family Planning, Beijing, China
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  • Wei-Jie Zhao,

    1. State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China
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  • Peng Li,

    1. Department of Genetics, National Research Institute for Family Planning, Beijing, China
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  • Guang-Yu Zhao,

    1. Fuzhou Southeast Eye Hospital, Fuzhou, Fujian, China
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  • Yi Tong,

    1. Fuzhou Southeast Eye Hospital, Fuzhou, Fujian, China
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  • Fan-Chen Bao,

    1. State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China
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  • Yan Ma,

    1. Graduate School of Peking Union Medical College, Beijing, China
    2. Department of Genetics, National Research Institute for Family Planning, Beijing, China
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  • Sha Wang,

    1. State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China
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  • Yong-Bin Yan,

    Corresponding author
    1. State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China
    • Yong-Bin Yan, School of Life Sciences, Tsinghua University, Beijing 100084, PR China

      Cai-Ling Lu, Department of Genetics, National Research Institute for Family planning, Beijing 100081, PR China

      Xu Ma, Xu Ma, Department of Genetics, Graduate School of Peking Union Medical College, National Research Institute for Family Planning, Beijing 100081, PR China

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  • Cai-Ling Lu,

    Corresponding author
    1. Graduate School of Peking Union Medical College, Beijing, China
    2. Department of Genetics, National Research Institute for Family Planning, Beijing, China
    • Yong-Bin Yan, School of Life Sciences, Tsinghua University, Beijing 100084, PR China

      Cai-Ling Lu, Department of Genetics, National Research Institute for Family planning, Beijing 100081, PR China

      Xu Ma, Xu Ma, Department of Genetics, Graduate School of Peking Union Medical College, National Research Institute for Family Planning, Beijing 100081, PR China

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  • Xu Ma

    Corresponding author
    1. Graduate School of Peking Union Medical College, Beijing, China
    2. Department of Genetics, National Research Institute for Family Planning, Beijing, China
    • Yong-Bin Yan, School of Life Sciences, Tsinghua University, Beijing 100084, PR China

      Cai-Ling Lu, Department of Genetics, National Research Institute for Family planning, Beijing 100081, PR China

      Xu Ma, Xu Ma, Department of Genetics, Graduate School of Peking Union Medical College, National Research Institute for Family Planning, Beijing 100081, PR China

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Abstract

Congenital cataract is one of the leading causes of human blindness. In this study, we identified a novel, heterozygous c.385G<T mutation in CRYGC that resulted in the substitution of a highly conserved glycine by cysteine at codon 129 (p.Gly129Cys) in a three-generation Chinese family with autosomal dominant congenital nuclear cataract by sequencing candidate genes. Using zebrafish as a model, we demonstrated that γC-crystallin p.Gly129Cys mutant caused the vacuole and the incomplete denucleation of lens, recapitulating the cataract phenotype in human beings. Molecular modeling and spectroscopic studies indicated that the mutation impaired the tertiary structure of the protein by modifying the H-bonding network in the C-terminal domain. The mutation led to a dramatic decrease in the thermal stability of γC-crystallin, and a significant increase in the propensity of aggregation when subject to storage at high concentrations, heat, and UV- irradiation stresses. Taken together, these results indicate that a novel γC-crystallin p.Gly129Cys mutation impaired the tertiary structure of the protein and caused cataract formation, which provides a new insight into how the mutation may affect the γC-crystallin structure, stability, and function. Our study also highlighted zebrafish as a valuable model tool for studying congenital inherited cataract. Hum Mutat 33:391–401, 2012. © 2011 Wiley Periodicals, Inc.

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