CPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix

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dc.contributor.authorBonet Fernández, Juan Manuel
dc.contributor.authorAroca Aguilar, José Daniel
dc.contributor.authorCorton Pérez, Marta
dc.contributor.authorRamírez Sebastián, Ana Isabel
dc.contributor.authorAlexandre Moreno, Susana
dc.contributor.authorGarcía Antón, María Teresa
dc.contributor.authorSalazar Corral, Juan José
dc.contributor.authorFerre Fernández, Jesús José
dc.contributor.authorAtienzar Aroca, Raquel
dc.contributor.authorVillaverde Montero, Cristina
dc.contributor.authorIancu, Ionut
dc.contributor.authorTamayo Durán, Alejandra
dc.contributor.authorMéndez Hernández, Carmen Dora
dc.contributor.authorMorales Fernández, Laura
dc.contributor.authorRojas López, Blanca
dc.contributor.authorAyuso García, Carmen
dc.contributor.authorCoca Prados, Miguel
dc.contributor.authorMartínez De La Casa Fernández-Borrella, José María
dc.contributor.authorGarcía Feijoo, Julián
dc.contributor.authorEscribano, Julio
dc.date.accessioned2023-06-16T15:17:08Z
dc.date.available2023-06-16T15:17:08Z
dc.date.issued2020-04-09
dc.descriptionReceived: 27 Januaury 2020; Accepted: 03 April 2020; Published: 09 April 2020
dc.description.abstractAbnormal 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.departmentUnidad Docente de Inmunología, Oftalmología y ORL
dc.description.facultyFac. de Óptica y Optometría
dc.description.refereedTRUE
dc.description.sponsorshipInstituto de Salud Carlos III
dc.description.sponsorshipMinisterio de Economía, Comercio y Empresa (España)
dc.description.sponsorshipComunidad de Madrid
dc.description.sponsorshipCentro de Investigación Biomédica en Red de Enfermedades Raras
dc.description.sponsorshipJunta de Comunidades de Castilla La Mancha
dc.description.sponsorshipUniversity Chair UAMIIS-FJD of Genomic Medicine
dc.description.sponsorshipPrograma Miguel Servet
dc.description.sponsorshipFundación Ramón Areces
dc.description.sponsorshipEuropean Regional Development Fund
dc.description.sponsorshipMinisterio de Educación, Formación Profesional y Deportes (España)
dc.description.sponsorshipFondo Europeo de Desarrollo Regional
dc.description.statuspub
dc.eprint.idhttps://eprints.ucm.es/id/eprint/60052
dc.identifier.citationBonet 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.doi10.1007/s00439-020-02164-0
dc.identifier.issn0340-6717
dc.identifier.officialurlhttps://doi.org/10.1007/s00439-020-02164-0
dc.identifier.relatedurlhttps://link.springer.com/article/10.1007/s00439-020-02164-0#rightslink
dc.identifier.urihttps://hdl.handle.net/20.500.14352/6178
dc.journal.titleHuman Genetics
dc.language.isoeng
dc.publisherSpringer-Verlag
dc.relation.projectID(PI15/01193; PI19/00208; RD16/0008/0019; OFTARED; RD16/0008/0004; RD16/0008/0005; PI17_01164;
dc.relation.projectIDSAF2013-46943-R
dc.relation.projectIDRAREGENOMICS-CM (B2017/BMD3721)
dc.relation.projectID(CIBERER 06/07/0036)
dc.relation.projectIDSBPLY/17/180501/000404
dc.relation.projectIDCPII17_00006
dc.relation.projectIDPREJCCM2016/28
dc.relation.projectIDPEJD-2018-PRE/BMD-9453
dc.relation.projectIDFPU 13/03308
dc.rights.accessRightsopen access
dc.subject.cdu617.7-007.681
dc.subject.cdu575:61
dc.subject.cdu617.7-07
dc.subject.keywordCPAMD8
dc.subject.keywordGenetics
dc.subject.keywordCongenital glaucoma
dc.subject.keywordOcular anterior segment
dc.subject.keywordExtracellular matrix
dc.subject.ucmGenética médica
dc.subject.ucmOftalmología
dc.subject.ucmAnatomía ocular
dc.subject.ucmTécnicas de la imagen
dc.subject.unesco2410.07 Genética Humana
dc.subject.unesco3201.09 Oftalmología
dc.titleCPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrixen
dc.typejournal article
dspace.entity.typePublication
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