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
T2 Matrix Metalloproteinase Genes and Glaucoma
A1 Tevar, Ángel
A1 Aroca Aguilar, José Daniel
A1 Bonet Fernández, Juan Manuel
A1 Atienzar Aroca, Raquel
A1 Campos Mollo, Ezequiel
A1 Morales Fernández, Laura
A1 Leal Palmer, Iñaki
A1 Coca Prados, Miguel
A1 Escribano, Julio
A1 Méndez Hernández, Carmen Dora
A1 Martínez De La Casa Fernández-Borrella, José María
A1 García Feijoo, Julián
AB Childhood glaucoma encompasses congenital and juvenile primary glaucoma, which are heterogeneous, uncommon, and irreversible optic neuropathies leading to visual impairment with 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 metalloproteinases-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.
YR 2024
FD 2024-02-13
LK https://hdl.handle.net/20.500.14352/101850
UL https://hdl.handle.net/20.500.14352/101850
LA eng
NO Tevar, A.; Aroca-Aguilar, J.; Bonet-Fernández, J.; Atienzar-Aroca, R.; Campos-Mollo, E.; Méndez-Hernández, C.; Morales-Fernández, L.; Leal Palmer, I.; Coca-Prados, M.; Martinez-de-la-Casa, J.; Garcia-Feijoo, J.; Escribano, J. The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease. Preprints 2024, 2024020752. https://doi.org/10.20944/preprints202402.0752.v1
NO European Regional Development Fund
NO Comunidad de Castilla-La Mancha (España)
NO Universidad de Castilla-La Mancha (España)
NO Comunidad Valenciana (España)
DS Docta Complutense
RD 26 abr 2025