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We have previously identified the genetic contribution of\n                    <jats:italic>SLC39A5<\/jats:italic>\n                    to nonsyndromic high myopia and demonstrated that disease\u2010related mutations of\n                    <jats:italic>SLC39A5<\/jats:italic>\n                    dysregulate the TGF\u2010\u03b2 pathway. In this study, the mechanisms underlying SLC39A5 involvement in the pathogenesis of high myopia are determined. We observed the morphogenesis and migration abnormalities of the SLC39A5\u00a0knockout (KO) human embryonic kidney cells (HEK293) and found a significant injury of ECM constituents. RNA\u2010seq and qRT\u2010PCR revealed the transcription decrease in\n                    <jats:italic>COL1A1<\/jats:italic>\n                    ,\n                    <jats:italic>COL2A1<\/jats:italic>\n                    ,\n                    <jats:italic>COL4A1<\/jats:italic>\n                    ,\n                    <jats:italic>FN1<\/jats:italic>\n                    and\n                    <jats:italic>LAMA1<\/jats:italic>\n                    in the KO cells. Further, we demonstrated that TGF\u2010\u03b2 signalling, the regulator of ECM, was inhibited in SLC39A5 depletion situation, wherein the activation of receptor Smads (R\u2010Smads) via phosphorylation was greatly blocked. SLC39A5 re\u2010expression reversed the phenotype of TGF\u2010\u03b2 signalling and ECM synthesis in the KO cells. The fact that TGF\u2010\u03b2 signalling was zinc\u2010regulated and that SLC39A5 was identified as a zinc transporter urged us to check the involvement of intracellular zinc in TGF\u2010\u03b2 signalling impairment. Finally, we determined that insufficient zinc chelation destabilized Smad proteins, which naturally inhibited TGF\u2010\u03b2 signalling. Overall, the SLC39A5 depletion\u2013induced zinc deficiency destabilized Smad proteins, which inhibited the TGF\u2010\u03b2 signalling and downstream ECM synthesis, thus contributing to the pathogenesis of high myopia. This discovery provides a deep insight into myopic development.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.16803","type":"journal-article","created":{"date-parts":[[2021,7,24]],"date-time":"2021-07-24T06:42:41Z","timestamp":1627108961000},"page":"8432-8441","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["SLC39A5 dysfunction impairs extracellular matrix synthesis in high myopia pathogenesis"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1605-7066","authenticated-orcid":false,"given":"Shanshan","family":"Dong","sequence":"first","affiliation":[{"name":"Center for Medical Genetics &amp; Hunan Key Laboratory of Medical Genetics School of Life Sciences Central South University Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Tian","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics &amp; Hunan Key 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