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Novel cataract-causing variant c.177dupC in c-MAF regulates the expression of crystallin genes for cell apoptosis via a mitochondria-dependent pathway

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Abstract

Congenital cataract (CC) is regarded as the most common hereditary ophthalmic disease in children. Mutations in CC-associated genes play important roles in CC formation, which provides the basis for molecular diagnosis and therapy. Among these CC-associated genes, v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (c-MAF) is considered an important transcription factor for eye and lens development. In this study, we recruited a three-generation Chinese Han family with CC. Gene sequencing revealed a novel duplication mutation in c-MAF (NM_005360.5: c.177dup) that caused frameshifting at residue 60 (p. M60fs) of c-MAF. Additionally, in the patient blood samples, the expression levels of related crystallin and noncrystallin genes confirmed that this novel duplication variant impaired the transactivation of c-MAF. Further functional analyses suggested that the c-MAF mutant induces the transcriptional inhibition of CRYAA and CRYGA and subsequently influences ME and G6PD expression levels, ultimately resulting in ROS generation and further leading to cell apoptosis via mitochondria-dependent pathways. In conclusion, we report a novel c-MAF heterozygous mutation that plays a vital role in CC formation in a Chinese family, broadening the genetic spectrum of CC.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (82000875) and the Natural Science Foundation of Henan Province, China (202300410397).

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Authors and Affiliations

  1. Ophthalmologic Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Li Li, Jian-Fei Yue, De-Qian Kong, Miao-Miao Sun, Ke Li & Guang-Ying Zheng

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  1. Li Li
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  2. Jian-Fei Yue
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  3. De-Qian Kong
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  4. Miao-Miao Sun
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  5. Ke Li
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  6. Guang-Ying Zheng
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Contributions

LL: Conceptualization, Methodology, Writing—original draft. J-FY: Methodology, Visualization, Validation. D-QK: Methodology, Visualization, Investigation. M-MS: Methodology, Visualization, Formal analysis. KL: Investigation, Data curation, Validation, Resources. G-YZ: Project administration, Writing—review and editing, Supervision.

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Correspondence to Li Li or Guang-Ying Zheng.

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The authors declare that they have no known competing or noncompeting financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Communicated by Shuhua Xu.

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Li, L., Yue, JF., Kong, DQ. et al. Novel cataract-causing variant c.177dupC in c-MAF regulates the expression of crystallin genes for cell apoptosis via a mitochondria-dependent pathway. Mol Genet Genomics 298, 495–506 (2023). https://doi.org/10.1007/s00438-022-01982-3

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