{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:53:47Z","timestamp":1787313227991,"version":"build-2736575974"},"reference-count":83,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T00:00:00Z","timestamp":1701216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["81770965"],"award-info":[{"award-number":["81770965"]}]},{"name":"National Natural Science Foundation of China","award":["81970837"],"award-info":[{"award-number":["81970837"]}]},{"name":"National Natural Science Foundation of China","award":["3030901010077"],"award-info":[{"award-number":["3030901010077"]}]},{"name":"Fundamental Research Fundus of the State Key Laboratory of Ophthalmology at Zhongshan Ophthalmic Center","award":["81770965"],"award-info":[{"award-number":["81770965"]}]},{"name":"Fundamental Research Fundus of the State Key Laboratory of Ophthalmology at Zhongshan Ophthalmic Center","award":["81970837"],"award-info":[{"award-number":["81970837"]}]},{"name":"Fundamental Research Fundus of the State Key Laboratory of Ophthalmology at Zhongshan Ophthalmic Center","award":["3030901010077"],"award-info":[{"award-number":["3030901010077"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thinning of the sclera happens in myopia eyes owing to extracellular matrix (ECM) remodeling, but the initiators of the ECM remodeling in myopia are mainly unknown. The matrix metalloproteinase (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs) regulate the homeostasis of the ECM. However, genetic studies of the MMPs and TIMPs in the occurrence of myopia are poor and limited. This study systematically investigated the association between twenty-nine genes of the TIMPs and MMPs families and early-onset high myopia (eoHM) based on whole exome sequencing data. Two TIMP4 heterozygous loss-of-function (LoF) variants, c.528C&gt;A in six patients and c.234_235insAA in one patient, were statistically enriched in 928 eoHM probands compared to that in 5469 non-high myopia control (p = 3.7 \u00d7 10\u22125) and that in the general population (p = 2.78 \u00d7 10\u22129). Consequently, the Timp4 gene editing rat was further evaluated to explore the possible role of Timp4 on ocular and myopia development. A series of ocular morphology abnormalities in a dose-dependent manner (Timp4\u2212\/\u2212 &lt; Timp4+\/\u2212 &lt; Timp4+\/+) were observed in a rat model, including the decline in the retinal thickness, the elongation in the axial length, more vulnerable to the form deprivation model, morphology changes in sclera collagen bundles, and the decrease in collagen contents of the sclera and retina. Electroretinogram revealed that the b-wave amplitudes of Timp4 defect rats were significantly reduced, consistent with the shorter length of the bipolar axons detected by HE and IF staining. Heterozygous LoF variants in the TIMP4 are associated with early onset high myopia, and the Timp4 defect disturbs ocular development by influencing the morphology and function of the ocular tissue.<\/jats:p>","DOI":"10.3390\/ijms242316928","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T09:00:18Z","timestamp":1701248418000},"page":"16928","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Defect of TIMP4 Is Associated with High Myopia and Participates in Rat Ocular Development in a Dose-Dependent Manner"],"prefix":"10.3390","volume":"24","author":[{"given":"Wenhui","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Yi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamin","family":"Ouyang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqing","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7508-848X","authenticated-orcid":false,"given":"Qingjiong","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.ophtha.2016.01.006","article-title":"Global Prevalence of Myopia and High Myopia and Temporal Trends from 2000 through 2050","volume":"123","author":"Holden","year":"2016","journal-title":"Ophthalmology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1097\/IAE.0000000000001489","article-title":"Overview of the Complications of high myopia","volume":"37","author":"Ikuno","year":"2017","journal-title":"Retina"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s10654-019-00512-7","article-title":"Interaction between lifestyle and genetic susceptibility in myopia: The Generation R study","volume":"34","author":"Enthoven","year":"2019","journal-title":"Eur. 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