RT Journal Article
T1 The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease
A1 Tevar A, 
A1 Aroca-Aguilar JD, 
A1 Bonet-Fernández JM, 
A1 Atienzar-Aroca R, 
A1 Campos-Mollo E, 
A1 Méndez Hernández, Carmen Dora
A1 Morales-Fernández L, 
A1 Leal Palmer I, 
A1 Coca-Prados M, 
A1 Martínez De La Casa Fernández-Borrella, José María
A1 García Feijoo, Julián
A1 Escribano J, 
AB Childhood glaucoma encompasses congenital and juvenile primary glaucoma, which are heterogeneous, uncommon, and irreversible optic neuropathies leading to visual impairment with a poorly understood genetic basis. 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’s 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.
PB MDPI
YR 2024
FD 2024-05
LK https://hdl.handle.net/20.500.14352/122140
UL https://hdl.handle.net/20.500.14352/122140
LA eng
NO Tevar, A., Aroca-Aguilar, J.-D., Bonet-Fernández, J.-M., Atienzar-Aroca, R., Campos-Mollo, E., Méndez-Hernández, C., Morales-Fernández, L., Leal Palmer, I., Coca-Prados, M., Martinez-de-la-Casa, J.-M., Garcia-Feijoo, J., & Escribano, J. (2024). The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease. International Journal of Molecular Sciences, 25(11), 5757. https://doi.org/10.3390/ijms25115757
NO Instituto de Salud Carlos III
NO Consejería de Ciencia y Tecnología de la Junta de Comunidades de Castilla-La Mancha
NO Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana
DS Docta Complutense
RD 17 dic 2025