Abstract
Presenile cataract is a relatively rare type of cataract, but its genetic mechanisms are currently not well understood. The precise identification of these causative genes is crucial for effective genetic counseling for patients and their families. The aim of our study was to identify the causative gene associated with presenile cataract in a Chinese family. In February 2020, a four-generation pedigree of presenile cataract patients was recruited at the 2nd Affiliated Hospital of Kunming Medical University. One patient and her healthy husband from the family underwent whole exome sequencing. The variant was validated through sanger sequencing, and co-segregation analysis was conducted in all family members to assess its pathogenicity. Molecular dynamics simulation (MDS) was used to analyze the conformation of both the wild type and pathogenic mutant loci p.Y153H of CRYBA2. We identified presenile cataract in the pedigree, which follows an autosomal-dominant pattern of inheritance. The family includes five clinically affected patients who all developed presenile cataract between the ages from 24 to 30. We confirmed the pathogenicity of a heterozygous missense variant (NM_057093:c.457T >C) in CRYBA2 within this family. The affected amino acid demonstrates high conservation across species. Subsequent sanger sequencing confirmed co-segregation of the disease in all family members. MDS analysis revealed that the p.Y153H mutant disrupted hydrogen bond formation between Y153 and R193 within the two β-strands of the fourth Greek key domain, leading to destabilization of the βA2-crystallin. In conclusion, a novel causative mutation (NM_057093:c.457T>C) in CRYBA2 might contribute to autosomal dominant presenile cataract.
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The datasets collected and/or analyzed during the current study are available from the corresponding author upon request.
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Acknowledgements
All authors gratefully acknowledge the family for their participation in this research study.
Funding
This work was supported by the scientific research fund project of the Yunnan Education Department (2023Y0637), the Applied Basic Research Program (Kunming Medical University Special Project) of Yunnan Province [grant No. 2019FE001(-070)], and the Science and Technology Program of the 2nd affiliated Hospital of Kunming Medical University (grant NO. 2020yk001).
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YSH and XZ conceived designed, review & editing the study. HAY, FL, XYF, XD, and LPY conducted the experiments. YBK, GJW, MJM, and HAY collected the data, processed data analysis and interpretation of data. HAY wrote the original manuscript. YSH, XZ, and YBK critically revising the manuscript. All authors have reviewed and approved the final manuscript.
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The current study was approved by the Institutional Review Boards of the 2nd Affiliated Hospital of Kunming Medical University. Written informed consents were obtained from all investigated individuals prior to the study. Before enrollment, the patients or their guardians gave informed consent.
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Communicated by Shuhua Xu.
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Kong, Y., Yi, H., Li, F. et al. A novel missense mutation in the CRYBA2 caused autosomal dominant presenile cataract in a Chinese family. Mol Genet Genomics 298, 1237–1244 (2023). https://doi.org/10.1007/s00438-023-02052-y
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DOI: https://doi.org/10.1007/s00438-023-02052-y