The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease

Angel Tevar; José-Daniel Aroca-Aguilar; Juan-Manuel Bonet-Fernández; Raquel Atienzar-Aroca; Ezequiel Campos-Mollo; Carmen-Dora Méndez-Hernández; Laura Morales-Fernández; Iñaki Leal Palmer; Miguel Coca-Prados; Jose-Maria Martinez-de-la-Casa; Julian Garcia-Feijoo; Julio Escribano

doi:10.20944/preprints202402.0752.v1

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preprints.org > medicine and pharmacology > ophthalmology > doi: 10.20944/preprints202402.0752.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease

Angel Tevar

José-Daniel Aroca-Aguilar

Juan-Manuel Bonet-Fernández

Raquel Atienzar-Aroca

Ezequiel Campos-Mollo

Carmen-Dora Méndez-Hernández

Laura Morales-Fernández

Iñaki Leal Palmer

Miguel Coca-Prados

Jose-Maria Martinez-de-la-Casa

Julian Garcia-Feijoo

Julio Escribano

Version 1 : Received: 13 February 2024 / Approved: 13 February 2024 / Online: 13 February 2024 (15:28:28 CET)

How to cite: 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 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

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MDPI and ACS Style

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

APA Style

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. (2024). The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease. Preprints. https://doi.org/10.20944/preprints202402.0752.v1

Chicago/Turabian Style

Tevar, A., Julian Garcia-Feijoo and Julio Escribano. 2024 "The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease" Preprints. https://doi.org/10.20944/preprints202402.0752.v1

Abstract

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.

Keywords

Glaucoma; Matrix Metalloproteinases; Multifactorial Inheritance.

Subject

Medicine and Pharmacology, Ophthalmology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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