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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&gt;T and c.-187G&gt;C in\n                    <jats:italic>PRSS56<\/jats:italic>\n                    , 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&gt;T and knock-in mice (c.-155G&gt;T, corresponding to human c.-187G&gt;T) that faithfully recapitulate myopia phenotypes. Noncoding\n                    <jats:italic>PRSS56<\/jats:italic>\n                    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\n                    <jats:italic>Prss56<\/jats:italic>\n                    expression, and short-wave light exposure reduced\n                    <jats:italic>Prss56<\/jats:italic>\n                    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\n                    <jats:italic>PRSS56<\/jats:italic>\n                    variants in HM and highlight PRSS56 as a promising therapeutic target for juvenile HM.\n                  <\/jats:p>","DOI":"10.1038\/s41422-026-01241-9","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T01:31:07Z","timestamp":1775007067000},"page":"567-581","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Increased PRSS56 expression is a causal factor and therapeutic target for human axial high myopia"],"prefix":"10.1038","volume":"36","author":[{"given":"Boxuan","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijia","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kefu","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofen","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renyuan","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoli","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongfeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingqian","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2115-4175","authenticated-orcid":false,"given":"Xiangyu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9422-5264","authenticated-orcid":false,"given":"Hongyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"1241_CR1","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1016\/S0140-6736(12)60272-4","volume":"379","author":"IG Morgan","year":"2012","unstructured":"Morgan, I. 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