RT Journal Article
T1 CPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix
A1 Bonet Fernández, Juan Manuel
A1 Aroca Aguilar, José Daniel
A1 Corton Pérez, Marta
A1 Ramírez Sebastián, Ana Isabel
A1 Alexandre Moreno, Susana
A1 García Antón, María Teresa
A1 Salazar Corral, Juan José
A1 Ferre Fernández, Jesús José
A1 Atienzar Aroca, Raquel
A1 Villaverde Montero, Cristina
A1 Iancu, Ionut
A1 Tamayo Durán, Alejandra
A1 Méndez Hernández, Carmen Dora
A1 Morales Fernández, Laura
A1 Rojas López, Blanca
A1 Ayuso García, Carmen
A1 Coca Prados, Miguel
A1 Martínez de la Casa, José María
A1 García Feijoo, Julián
A1 Escribano, Julio
AB 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.
PB Springer-Verlag
SN 0340-6717
YR 2020
FD 2020-04-09
LK https://hdl.handle.net/20.500.14352/6178
UL https://hdl.handle.net/20.500.14352/6178
LA eng
NO Received: 27 Januaury 2020; Accepted: 03 April 2020; Published: 09 April 2020
NO Instituto de Salud Carlos III/FEDER
NO Ministerio de Economía y Competitividad (MINECO)
NO Comunidad de Madrid
NO CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras)
NO Junta de Comunidades de Castilla La Mancha
NO University Chair UAMIIS-FJD of Genomic Medicine
NO Programa Miguel Servet
NO Fundación Ramón Areces
NO European Regional Development Fund (ERDF)
NO Ministerio de Educación, Cultura y Deporte de España
DS Docta Complutense
RD 15 may 2024