Abstract
Mutations in myelin regulatory factor (MYRF), a gene mapped to 11q12-q13.3, are responsible for autosomal dominant high hyperopia and seem to be associated with angle closure glaucoma, which is one of the leading causes of irreversible blindness worldwide. Whether there is a causal link from the MYRF mutations to the pathogenesis of primary angle-closure glaucoma (PACG) remains unclear at this time. Six truncation mutations, including five novel and one previously reported, in MYRF are identified in seven new probands with hyperopia, of whom all six adults have glaucoma, further confirming the association of MYRF mutations with PACG. Immunofluorescence microscopy demonstrates enriched expression of MYRF in the ciliary body and ganglion cell layer in humans and mice. Myrfmut/+ mice have elevated IOP and fewer ganglion cells along with thinner retinal nerve fiber layer with ganglion cell layer than wild-type. Transcriptome sequencing of Myrfmut/+ retinas shows downregulation of Dnmt3a, a gene previously associated with PACG. Co-immunoprecipitation demonstrates a physical association of DNMT3A with MYRF. DNA methylation sequencing identifies several glaucoma-related cell events in Myrfmut/+ retinas. The interaction between MYRF and DNMT3A underlies MYRF-associated PACG and provides clues for pursuing further investigation into the pathogenesis of PACG and therapeutic target.
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Data availability
Data supporting the present study are available from the corresponding author upon reasonable request.
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Acknowledgements
We thank all patients and their relatives for their participation in this study. We thank Mengsheng Qi for gifting the plasmid. We thank the staff of Core Facilities at State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center for technical support.
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This work was supported by grants from the National Natural Science Foundation of China (82171056).
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QZ designed the study. XX, SL, XL, YW, and QZ recruited patients. WS, XL, YW, and QZ obtained the clinical data. XX, SL, and QZ performed whole exome analysis. JO, WS, JFH, and QZ performed the bioinformatic analysis. JO, HJ, XL, YW, YJ, and ZT conducted the experiments. JO, WS, HS, JFH, ZT and QZ discussed the results and wrote the manuscript. All authors reviewed and approved the manuscript.
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All animal experiments were approved by the Zhongshan Ophthalmic Center, Sun Yat-sen University Animal Care and Use Committee (reference number: SYXK(YUE)2020–0058) and followed its guidelines as well as the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research. The use of postmortem human ocular tissues was approved by the Ethics Committee of Zhongshan Ophthalmic Center, Sun Yat-sen University for the two from the Eye Bank of Guangdong Province and by the Institutional Review Board of University of California Irvine as “non-human subjects” for those from NDRI.
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Ouyang, J., Sun, W., Shen, H. et al. Truncation mutations in MYRF underlie primary angle closure glaucoma. Hum Genet 142, 103–123 (2023). https://doi.org/10.1007/s00439-022-02487-0
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DOI: https://doi.org/10.1007/s00439-022-02487-0