CHST5 gene mutations contribute to high myopia by disrupting collagen fiber organization.

High myopia (HM) is a leading cause of irreversible vision loss in working-age adults. Its pathogenesis is characterized by alterations in the microstructure and composition of collagen fibers, and genetic factors make a substantial contribution. In this study, we identify carbohydrate sulfotransferase 5 (CHST5) as a candidate gene for HM in humans and mice, with its mutations disrupting collagen fiber organization. The c.444C>A (p.S148R) variant in CHST5, a gene critical for sulfating corneal keratan sulfate (KS), completely co-segregates with HM in a Chinese family. Screening of CHST5 variants in 320 HM patients identifies two additional ones. We further find that Chst5 is expressed primarily in the cornea and sclera of mouse ocular tissues, and that the mutant protein CHST5S148R loses its Golgi localization. Homozygous mutant Chst5S126R mice exhibit HM phenotypes, including myopic refractive error (RE), significantly thinner sclera and cornea, notable microstructural changes in scleral and corneal collagen fibers, and shorter corneal KS chains. Our findings suggest that CHST5 NM_024533.5 c.444C>A (p.S148R) causes loss of proper protein localization, likely impairing its sulfotransferase function. This defect disrupts the organization of corneal and scleral collagen fibers and ultimately contributes to the development and progression of HM.