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Altered Ocular Fibrillin Microfibril Composition in Mice With a Glaucoma-Causing Mutation of Adamts10

PURPOSE: Previously, we identified a G661R mutation of ADAMTS10 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 10) as being disease causative in a colony of Beagles with inherited primary open-angle glaucoma (POAG). Mutations in ADAMTS10 are known to cause Weill–Marchesani...

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Autores principales: Wu, Hang-Jing, Mortlock, Douglas P., Kuchtey, Rachel W., Kuchtey, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383930/
https://www.ncbi.nlm.nih.gov/pubmed/34424262
http://dx.doi.org/10.1167/iovs.62.10.26
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author Wu, Hang-Jing
Mortlock, Douglas P.
Kuchtey, Rachel W.
Kuchtey, John
author_facet Wu, Hang-Jing
Mortlock, Douglas P.
Kuchtey, Rachel W.
Kuchtey, John
author_sort Wu, Hang-Jing
collection PubMed
description PURPOSE: Previously, we identified a G661R mutation of ADAMTS10 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 10) as being disease causative in a colony of Beagles with inherited primary open-angle glaucoma (POAG). Mutations in ADAMTS10 are known to cause Weill–Marchesani syndrome (WMS), which is also caused by mutations in the fibrillin-1 gene (FBN1), suggesting functional linkage between ADAMTS10 and fibrillin-1, the principal component of microfibrils. Here, we established a mouse line with the G661R mutation of Adamts10 (Adamts10(G661R/G661R)) to determine if they develop features of WMS and alterations of ocular fibrillin microfibrils. METHODS: Intraocular pressure (IOP) was measured using a TonoLab rebound tonometer. Central cornea thickness (CCT), anterior chamber depth (ACD) and axial length (AL) of the eye were examined by spectral-domain optical coherence tomography. Sagittal eye sections from mice at postnatal day 10 (P10) and at 3 and 24 months of age were stained with antibodies against fibrillin-1, fibrillin-2, and ADAMTS10. RESULTS: IOP was not elevated in Adamts10(G661R/G661R) mice. Adamts10(G661R/G661R) mice had smaller bodies, thicker CCT, and shallower ACD compared to wild-type mice but normal AL. Adamts10(G661R/G661R) mice displayed persistent fibrillin-2 and enhanced fibrillin-1 immunofluorescence in the lens zonules and in the hyaloid vasculature and its remnants in the vitreous. CONCLUSIONS: Adamts10(G661R/G661R) mice recapitulate the short stature and ocular phenotypes of WMS. The altered fibrillin-1 and fibrillin-2 immunoactivity in Adamts10(G661R/G661R) mice suggests that the G661R mutation of Adamts10 perturbs regulation of the fibrillin isotype composition of microfibrils in the mouse eye.
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spelling pubmed-83839302021-09-07 Altered Ocular Fibrillin Microfibril Composition in Mice With a Glaucoma-Causing Mutation of Adamts10 Wu, Hang-Jing Mortlock, Douglas P. Kuchtey, Rachel W. Kuchtey, John Invest Ophthalmol Vis Sci Glaucoma PURPOSE: Previously, we identified a G661R mutation of ADAMTS10 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 10) as being disease causative in a colony of Beagles with inherited primary open-angle glaucoma (POAG). Mutations in ADAMTS10 are known to cause Weill–Marchesani syndrome (WMS), which is also caused by mutations in the fibrillin-1 gene (FBN1), suggesting functional linkage between ADAMTS10 and fibrillin-1, the principal component of microfibrils. Here, we established a mouse line with the G661R mutation of Adamts10 (Adamts10(G661R/G661R)) to determine if they develop features of WMS and alterations of ocular fibrillin microfibrils. METHODS: Intraocular pressure (IOP) was measured using a TonoLab rebound tonometer. Central cornea thickness (CCT), anterior chamber depth (ACD) and axial length (AL) of the eye were examined by spectral-domain optical coherence tomography. Sagittal eye sections from mice at postnatal day 10 (P10) and at 3 and 24 months of age were stained with antibodies against fibrillin-1, fibrillin-2, and ADAMTS10. RESULTS: IOP was not elevated in Adamts10(G661R/G661R) mice. Adamts10(G661R/G661R) mice had smaller bodies, thicker CCT, and shallower ACD compared to wild-type mice but normal AL. Adamts10(G661R/G661R) mice displayed persistent fibrillin-2 and enhanced fibrillin-1 immunofluorescence in the lens zonules and in the hyaloid vasculature and its remnants in the vitreous. CONCLUSIONS: Adamts10(G661R/G661R) mice recapitulate the short stature and ocular phenotypes of WMS. The altered fibrillin-1 and fibrillin-2 immunoactivity in Adamts10(G661R/G661R) mice suggests that the G661R mutation of Adamts10 perturbs regulation of the fibrillin isotype composition of microfibrils in the mouse eye. The Association for Research in Vision and Ophthalmology 2021-08-23 /pmc/articles/PMC8383930/ /pubmed/34424262 http://dx.doi.org/10.1167/iovs.62.10.26 Text en Copyright 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Glaucoma
Wu, Hang-Jing
Mortlock, Douglas P.
Kuchtey, Rachel W.
Kuchtey, John
Altered Ocular Fibrillin Microfibril Composition in Mice With a Glaucoma-Causing Mutation of Adamts10
title Altered Ocular Fibrillin Microfibril Composition in Mice With a Glaucoma-Causing Mutation of Adamts10
title_full Altered Ocular Fibrillin Microfibril Composition in Mice With a Glaucoma-Causing Mutation of Adamts10
title_fullStr Altered Ocular Fibrillin Microfibril Composition in Mice With a Glaucoma-Causing Mutation of Adamts10
title_full_unstemmed Altered Ocular Fibrillin Microfibril Composition in Mice With a Glaucoma-Causing Mutation of Adamts10
title_short Altered Ocular Fibrillin Microfibril Composition in Mice With a Glaucoma-Causing Mutation of Adamts10
title_sort altered ocular fibrillin microfibril composition in mice with a glaucoma-causing mutation of adamts10
topic Glaucoma
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383930/
https://www.ncbi.nlm.nih.gov/pubmed/34424262
http://dx.doi.org/10.1167/iovs.62.10.26
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