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Our goal was to identify gene variants associated with these glaucoma types by assessing the mutational burden in 76 matrix metalloproteinase-related genes. We studied 101 childhood glaucoma patients with no identified monogenic alterations using next-generation sequencing. Gene expression was assessed through immunohistochemistry. Functional analysis of selected gene variants was conducted in cultured cells and in zebrafish. Patients presented a higher proportion of rare variants in four metalloproteinase-related genes, including CPAMD8 and ADAMTSL4, compared to controls. ADAMTSL4 protein expression was observed in the anterior segment of both the adult human and zebrafish larvae\u2019s eye, including tissues associated with glaucoma. In HEK-293T cells, expression of four ADAMTSL4 variants identified in this study showed that two variants (p.Arg774Trp and p.Arg98Trp) accumulated intracellularly, inducing endoplasmic reticulum stress. Additionally, overexpressing these ADAMTSL4 variants in zebrafish embryos confirmed partial loss-of-function effects for p.Ser719Leu and p.Arg1083His. Double heterozygous functional suppression of adamtsl4 and cpamd8 zebrafish orthologs resulted in reduced volume of both the anterior eye chamber and lens within the chamber, supporting a genetic interaction between these genes. Our findings suggest that accumulation of partial functional defects in matrix metalloproteinase-related genes may contribute to increased susceptibility to early-onset glaucoma and provide further evidence supporting the notion of a complex genetic inheritance pattern underlying the disease.<\/jats:p>","DOI":"10.3390\/ijms25115757","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T10:12:27Z","timestamp":1716804747000},"page":"5757","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease"],"prefix":"10.3390","volume":"25","author":[{"given":"Angel","family":"Tevar","sequence":"first","affiliation":[{"name":"\u00c1rea de Gen\u00e9tica, Facultad de Medicina de Albacete, Universidad de Castilla-La Mancha, 02006 Albacete, 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Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"},{"name":"Instituto de Investigaciones Oftalmol\u00f3gicas Ram\u00f3n Castroviejo, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Morales-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality (OFTARED), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Servicio de Oftalmolog\u00eda, Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"},{"name":"Instituto de Investigaciones Oftalmol\u00f3gicas Ram\u00f3n Castroviejo, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I\u00f1aki","family":"Leal 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