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: Tevar A, Aroca-Aguilar JD, Bonet-Fernández JM, Atienzar-Aroca R, Campos-Mollo E, Méndez Hernández, Carmen Dora, Morales-Fernández L, Leal Palmer I, Coca-Prados M, Martínez De La Casa Fernández-Borrella, José María, García Feijoo, Julián, Escribano J
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/122140
Acceso en línea:https://hdl.handle.net/20.500.14352/122140
Access Level:acceso abierto
Palabra clave:617.7-007.681
Glaucoma
Matrix metalloproteinases
Multifactorial inheritance
Genética médica
Oftalmología
2409.02 Ingeniería Genética
3201.09 Oftalmología
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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 DiseaseTevar AAroca-Aguilar JDBonet-Fernández JMAtienzar-Aroca RCampos-Mollo EMéndez Hernández, Carmen DoraMorales-Fernández LLeal Palmer ICoca-Prados MMartínez De La Casa Fernández-Borrella, José MaríaGarcía Feijoo, JuliánEscribano J617.7-007.681GlaucomaMatrix metalloproteinasesMultifactorial inheritanceGenética médicaOftalmología2409.02 Ingeniería Genética3201.09 OftalmologíaChildhood 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.MDPIUniversidad Complutense de Madrid20242024-05-0120242024-05-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/122140reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengMinisterio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available RD16%2F0008%2F0019 OFTAREDInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII) PI19%2F00208 ANALISIS DE LAS BASES GENETICAS Y MOLECULARES DEL GLAUCOMA CONGENITO Y JUVENIL: IMPLICACIONES DIAGNOSTICAS Y TERAPEUTICASMinisterio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available RD16%2F0008%2F0004 OFTAREDInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII) PI19%2F01431 ANALISIS DE LAS BASES GENETICAS Y MOLECULARES DEL GLAUCOMA CONGENITO Y JUVENIL: IMPLICACIONES DIAGNOSTICAS Y TERAPEUTICASCYM SBPLY 17 000404UCLM 2022-GRIN-34136 Not availableUCLM 2020-PREDUCLM-16605 Not availableUGP UGP-21-227 Not availableopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1221402026-06-02T12:44:21Z
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
Tevar A
617.7-007.681
Glaucoma
Matrix metalloproteinases
Multifactorial inheritance
Genética médica
Oftalmología
2409.02 Ingeniería Genética
3201.09 Oftalmología
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 Tevar A
Aroca-Aguilar JD
Bonet-Fernández JM
Atienzar-Aroca R
Campos-Mollo E
Méndez Hernández, Carmen Dora
Morales-Fernández L
Leal Palmer I
Coca-Prados M
Martínez De La Casa Fernández-Borrella, José María
García Feijoo, Julián
Escribano J
author Tevar A
author_facet Tevar A
Aroca-Aguilar JD
Bonet-Fernández JM
Atienzar-Aroca R
Campos-Mollo E
Méndez Hernández, Carmen Dora
Morales-Fernández L
Leal Palmer I
Coca-Prados M
Martínez De La Casa Fernández-Borrella, José María
García Feijoo, Julián
Escribano J
author_role author
author2 Aroca-Aguilar JD
Bonet-Fernández JM
Atienzar-Aroca R
Campos-Mollo E
Méndez Hernández, Carmen Dora
Morales-Fernández L
Leal Palmer I
Coca-Prados M
Martínez De La Casa Fernández-Borrella, José María
García Feijoo, Julián
Escribano J
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 617.7-007.681
Glaucoma
Matrix metalloproteinases
Multifactorial inheritance
Genética médica
Oftalmología
2409.02 Ingeniería Genética
3201.09 Oftalmología
topic 617.7-007.681
Glaucoma
Matrix metalloproteinases
Multifactorial inheritance
Genética médica
Oftalmología
2409.02 Ingeniería Genética
3201.09 Oftalmología
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
2024-05-01
2024
2024-05-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/122140
url https://hdl.handle.net/20.500.14352/122140
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available RD16%2F0008%2F0019 OFTARED
Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII) PI19%2F00208 ANALISIS DE LAS BASES GENETICAS Y MOLECULARES DEL GLAUCOMA CONGENITO Y JUVENIL: IMPLICACIONES DIAGNOSTICAS Y TERAPEUTICAS
Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available RD16%2F0008%2F0004 OFTARED
Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII) PI19%2F01431 ANALISIS DE LAS BASES GENETICAS Y MOLECULARES DEL GLAUCOMA CONGENITO Y JUVENIL: IMPLICACIONES DIAGNOSTICAS Y TERAPEUTICAS
CYM SBPLY 17 000404
UCLM 2022-GRIN-34136 Not available
UCLM 2020-PREDUCLM-16605 Not available
UGP UGP-21-227 Not available
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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