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

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 assessin...

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Autores: Tévar Saiz, Ángel, Aroca Aguilar, José Daniel, Bonet Fernández, Juan Manuel, Atiénzar Aroca, Raquel, Campos Mollo, Ezequiel, Méndez Hernández, Carmen, Morales Fernández, Laura, Leal Palmer, Iñaki, Coca Prados, Miguel, Martínez de la Casa Fernández-Borrella, José María, García Feijoo, Julián, Escribano Martínez, Julio
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universidad de Castilla-La Mancha
Repositorio:RUIdeRA. Repositorio Institucional de la UCLM
OAI Identifier:oai:ruidera.uclm.es:10578/42031
Acceso en línea:https://doi.org/10.3390/ijms25115757
https://hdl.handle.net/10578/42031
Access Level:acceso abierto
Palabra clave:Glaucoma
Matrix metalloproteinases
Multifactorial inheritance
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spelling The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the DiseaseTévar Saiz, ÁngelAroca Aguilar, José DanielBonet Fernández, Juan ManuelAtiénzar Aroca, RaquelCampos Mollo, EzequielMéndez Hernández, CarmenMorales Fernández, LauraLeal Palmer, IñakiCoca Prados, MiguelMartínez de la Casa Fernández-Borrella, José MaríaGarcía Feijoo, JuliánEscribano Martínez, JulioGlaucomaMatrix metalloproteinasesMultifactorial inheritanceChildhood 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.MDPI202520252024info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttps://doi.org/10.3390/ijms25115757https://hdl.handle.net/10578/42031reponame:RUIdeRA. Repositorio Institucional de la UCLMinstname:Universidad de Castilla-La ManchaInglésRD16/0008/0019PI19/00208RD16/0008/0004PI19/01431SBPLY/17/180501/0004042022-GRIN-341362020-PREDUCLM-16605UGP-21-227info:eu-repo/semantics/openAccessoai:ruidera.uclm.es:10578/420312026-05-27T07:36:41Z
dc.title.none.fl_str_mv The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease
title The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease
spellingShingle The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease
Tévar Saiz, Ángel
Glaucoma
Matrix metalloproteinases
Multifactorial inheritance
title_short The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease
title_full The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease
title_fullStr The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease
title_full_unstemmed The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease
title_sort The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease
dc.creator.none.fl_str_mv Tévar Saiz, Ángel
Aroca Aguilar, José Daniel
Bonet Fernández, Juan Manuel
Atiénzar Aroca, Raquel
Campos Mollo, Ezequiel
Méndez Hernández, Carmen
Morales Fernández, Laura
Leal Palmer, Iñaki
Coca Prados, Miguel
Martínez de la Casa Fernández-Borrella, José María
García Feijoo, Julián
Escribano Martínez, Julio
author Tévar Saiz, Ángel
author_facet Tévar Saiz, Ángel
Aroca Aguilar, José Daniel
Bonet Fernández, Juan Manuel
Atiénzar Aroca, Raquel
Campos Mollo, Ezequiel
Méndez Hernández, Carmen
Morales Fernández, Laura
Leal Palmer, Iñaki
Coca Prados, Miguel
Martínez de la Casa Fernández-Borrella, José María
García Feijoo, Julián
Escribano Martínez, Julio
author_role author
author2 Aroca Aguilar, José Daniel
Bonet Fernández, Juan Manuel
Atiénzar Aroca, Raquel
Campos Mollo, Ezequiel
Méndez Hernández, Carmen
Morales Fernández, Laura
Leal Palmer, Iñaki
Coca Prados, Miguel
Martínez de la Casa Fernández-Borrella, José María
García Feijoo, Julián
Escribano Martínez, Julio
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Glaucoma
Matrix metalloproteinases
Multifactorial inheritance
topic Glaucoma
Matrix metalloproteinases
Multifactorial inheritance
description 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.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://doi.org/10.3390/ijms25115757
https://hdl.handle.net/10578/42031
url https://doi.org/10.3390/ijms25115757
https://hdl.handle.net/10578/42031
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv RD16/0008/0019
PI19/00208
RD16/0008/0004
PI19/01431
SBPLY/17/180501/000404
2022-GRIN-34136
2020-PREDUCLM-16605
UGP-21-227
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:RUIdeRA. Repositorio Institucional de la UCLM
instname:Universidad de Castilla-La Mancha
instname_str Universidad de Castilla-La Mancha
reponame_str RUIdeRA. Repositorio Institucional de la UCLM
collection RUIdeRA. Repositorio Institucional de la UCLM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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