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Increased PRSS56 expression is a causal factor and therapeutic target for human axial high myopia

Boxuan Wu^1,2,† , Weijia Zeng^1,† , Kefu Tang^1,† , Jiawei Xiong^3,† , Xiaofen Mo³ , Qing Fu⁴ , Dan Fu³ , Renyuan Chu³ , Guoli Zhao⁵ , Lei Lu¹ , Zhongfeng Wang⁵ , Lingqian Wu⁶ , Zhiqiang Yu^3,* , Xiangyu Zhou^1,* , Hongyan Wang^1,2,7,*

¹Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
²Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
³Eye and ENT Hospital of Fudan University, NHC Key Laboratory of Myopia, Shanghai, China
⁴Department of Ophthalmology, Huashan Hospital of Fudan University, Shanghai, China
⁵State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
⁶The Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha, Hunan, China
⁷Children’s Hospital of Fudan University, Shanghai, China
^†These authors contributed equally: Boxuan Wu, Weijia Zeng, Kefu Tang, Jiawei Xiong
* Correspondence: Zhiqiang Yu(zhqyu@21cn.com)Xiangyu Zhou(zhou_xiangyu@fudan.edu.cn)Hongyan Wang(wanghylab@fudan.edu.cn)

High myopia (HM), characterized by significant ocular axial length elongation, affects hundreds of millions of people and is often inherited, particularly in cases that develop during childhood or adolescence. Although numerous myopia loci (MYP) have been identified, most causative genes remain undefined. Here, we analyzed two large HM pedigrees and refined the critical region through haplotype linkage analysis to a 3.9-Mb interval on 2q37.1, which was previously reported as MYP12 with an unknown pathogenic gene. Whole-genome sequencing identified the noncoding promoter variants c.-187G>T and c.-187G>C in PRSS56, encoding a trypsin-like serine protease, which exclusively co-segregated with all affected members in both pedigrees. Compared with matched controls, increased PRSS56 expression was observed in both patient-derived iPSCs carrying c.-187G>T and knock-in mice (c.-155G>T, corresponding to human c.-187G>T) that faithfully recapitulate myopia phenotypes. Noncoding PRSS56 variants promote self-expression via enhanced binding to the transcription factor EGR1, as confirmed by dual-luciferase assays. Notably, we demonstrated that higher PRSS56 levels directly increase ocular axial length in a dose- and activity-dependent manner in multiple transgenic mouse models. Guinea pig myopia models consistently exhibited high Prss56 expression, and short-wave light exposure reduced Prss56 mRNA levels and attenuated further axial elongation. Mechanistically, higher PRSS56 expression was associated with reduced abundance of myosin-4 in the sclera and with molecular signatures of scleral remodeling, which were in turn correlated with axial elongation. In conclusion, our findings provide strong genetic and functional evidence for the pathogenic role of noncoding PRSS56 variants in HM and highlight PRSS56 as a promising therapeutic target for juvenile HM.

https://doi.org/10.1038/s41422-026-01241-9

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