CPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix
dc.contributor.author | Bonet Fernández, Juan Manuel | |
dc.contributor.author | Aroca Aguilar, José Daniel | |
dc.contributor.author | Corton Pérez, Marta | |
dc.contributor.author | Ramírez Sebastián, Ana Isabel | |
dc.contributor.author | Alexandre Moreno, Susana | |
dc.contributor.author | García Antón, María Teresa | |
dc.contributor.author | Salazar Corral, Juan José | |
dc.contributor.author | Ferre Fernández, Jesús José | |
dc.contributor.author | Atienzar Aroca, Raquel | |
dc.contributor.author | Villaverde Montero, Cristina | |
dc.contributor.author | Iancu, Ionut | |
dc.contributor.author | Tamayo Durán, Alejandra | |
dc.contributor.author | Méndez Hernández, Carmen Dora | |
dc.contributor.author | Morales Fernández, Laura | |
dc.contributor.author | Rojas López, Blanca | |
dc.contributor.author | Ayuso García, Carmen | |
dc.contributor.author | Coca Prados, Miguel | |
dc.contributor.author | Martínez De La Casa Fernández-Borrella, José María | |
dc.contributor.author | García Feijoo, Julián | |
dc.contributor.author | Escribano, Julio | |
dc.date.accessioned | 2023-06-16T15:17:08Z | |
dc.date.available | 2023-06-16T15:17:08Z | |
dc.date.issued | 2020-04-09 | |
dc.description | Received: 27 Januaury 2020; Accepted: 03 April 2020; Published: 09 April 2020 | |
dc.description.abstract | Abnormal development of the ocular anterior segment may lead to a spectrum of clinical phenotypes ranging from primary congenital glaucoma (PCG) to variable anterior segment dysgenesis (ASD). The main objective of this study was to identify the genetic alterations underlying recessive congenital glaucoma with ASD (CG-ASD). Next-generation DNA sequencing identified rare biallelic CPAMD8 variants in four patients with CG-ASD and in one case with PCG. CPAMD8 is a gene of unknown function and recently associated with ASD. Bioinformatic and in vitro functional evaluation of the variants using quantitative reverse transcription PCR and minigene analysis supported a loss-of-function pathogenic mechanism. Optical and electron microscopy of the trabeculectomy specimen from one of the CG-ASD cases revealed an abnormal anterior chamber angle, with altered extracellular matrix, and apoptotic trabecular meshwork cells. The CPAMD8 protein was immunodetected in adult human ocular fluids and anterior segment tissues involved in glaucoma and ASD (i.e., aqueous humor, non-pigmented ciliary epithelium, and iris muscles), as well as in periocular mesenchyme-like cells of zebrafish embryos. CRISPR/Cas9 disruption of this gene in F0 zebrafish embryos (96 hpf) resulted in varying degrees of gross developmental abnormalities, including microphthalmia, pharyngeal maldevelopment, and pericardial and periocular edemas. Optical and electron microscopy examination of these embryos showed iridocorneal angle hypoplasia (characterized by altered iris stroma cells, reduced anterior chamber, and collagen disorganized corneal stroma extracellular matrix), recapitulating some patients’ features. Our data support the notion that CPAMD8 loss-of-function underlies a spectrum of recessive CG-ASD phenotypes associated with extracellular matrix disorganization and provide new insights into the normal and disease roles of this gene. | en |
dc.description.department | Unidad Docente de Inmunología, Oftalmología y ORL | |
dc.description.faculty | Fac. de Óptica y Optometría | |
dc.description.refereed | TRUE | |
dc.description.sponsorship | Instituto de Salud Carlos III | |
dc.description.sponsorship | Ministerio de Economía, Comercio y Empresa (España) | |
dc.description.sponsorship | Comunidad de Madrid | |
dc.description.sponsorship | Centro de Investigación Biomédica en Red de Enfermedades Raras | |
dc.description.sponsorship | Junta de Comunidades de Castilla La Mancha | |
dc.description.sponsorship | University Chair UAMIIS-FJD of Genomic Medicine | |
dc.description.sponsorship | Programa Miguel Servet | |
dc.description.sponsorship | Fundación Ramón Areces | |
dc.description.sponsorship | European Regional Development Fund | |
dc.description.sponsorship | Ministerio de Educación, Formación Profesional y Deportes (España) | |
dc.description.sponsorship | Fondo Europeo de Desarrollo Regional | |
dc.description.status | pub | |
dc.eprint.id | https://eprints.ucm.es/id/eprint/60052 | |
dc.identifier.citation | Bonet Fernández, J. M., Aroca Aguilar, J. D., Corton Pérez, M. et al. «CPAMD8 Loss-of-Function Underlies Non-Dominant Congenital Glaucoma with Variable Anterior Segment Dysgenesis and Abnormal Extracellular Matrix». Human Genetics, vol. 139, n.o 10, octubre de 2020, pp. 1209-31. DOI.org (Crossref), https://doi.org/10.1007/s00439-020-02164-0. | |
dc.identifier.doi | 10.1007/s00439-020-02164-0 | |
dc.identifier.issn | 0340-6717 | |
dc.identifier.officialurl | https://doi.org/10.1007/s00439-020-02164-0 | |
dc.identifier.relatedurl | https://link.springer.com/article/10.1007/s00439-020-02164-0#rightslink | |
dc.identifier.uri | https://hdl.handle.net/20.500.14352/6178 | |
dc.journal.title | Human Genetics | |
dc.language.iso | eng | |
dc.publisher | Springer-Verlag | |
dc.relation.projectID | (PI15/01193; PI19/00208; RD16/0008/0019; OFTARED; RD16/0008/0004; RD16/0008/0005; PI17_01164; | |
dc.relation.projectID | SAF2013-46943-R | |
dc.relation.projectID | RAREGENOMICS-CM (B2017/BMD3721) | |
dc.relation.projectID | (CIBERER 06/07/0036) | |
dc.relation.projectID | SBPLY/17/180501/000404 | |
dc.relation.projectID | CPII17_00006 | |
dc.relation.projectID | PREJCCM2016/28 | |
dc.relation.projectID | PEJD-2018-PRE/BMD-9453 | |
dc.relation.projectID | FPU 13/03308 | |
dc.rights.accessRights | open access | |
dc.subject.cdu | 617.7-007.681 | |
dc.subject.cdu | 575:61 | |
dc.subject.cdu | 617.7-07 | |
dc.subject.keyword | CPAMD8 | |
dc.subject.keyword | Genetics | |
dc.subject.keyword | Congenital glaucoma | |
dc.subject.keyword | Ocular anterior segment | |
dc.subject.keyword | Extracellular matrix | |
dc.subject.ucm | Genética médica | |
dc.subject.ucm | Oftalmología | |
dc.subject.ucm | Anatomía ocular | |
dc.subject.ucm | Técnicas de la imagen | |
dc.subject.unesco | 2410.07 Genética Humana | |
dc.subject.unesco | 3201.09 Oftalmología | |
dc.title | CPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix | en |
dc.type | journal article | |
dspace.entity.type | Publication | |
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relation.isAuthorOfPublication.latestForDiscovery | 96eaf4c7-e811-480b-86ef-b2c0c3274977 |
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