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Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse

Cross, SH; Mckie, L; Keighren, M; West, K; Thaung, C; Davey, T; Soares, DC; ... Jackson, IJ; + view all (2019) Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse. Investigative Ophthalmology and Visual Science (IOVS) , 60 (8) pp. 2875-2887. 10.1167/iovs.18-25954. Green open access

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Abstract

Purpose: We previously found a dominant mutation, Rwhs, causing white spots on the retina accompanied by retinal folds. Here we identify the mutant gene to be Tmem98. In humans, mutations in the orthologous gene cause nanophthalmos. We modeled these mutations in mice and characterized the mutant eye phenotypes of these and Rwhs. // Methods: The Rwhs mutation was identified to be a missense mutation in Tmem98 by genetic mapping and sequencing. The human TMEM98 nanophthalmos missense mutations were made in the mouse gene by CRISPR-Cas9. Eyes were examined by indirect ophthalmoscopy and the retinas imaged using a retinal camera. Electroretinography was used to study retinal function. Histology, immunohistochemistry, and electron microscopy techniques were used to study adult eyes. // Results: An I135T mutation of Tmem98 causes the dominant Rwhs phenotype and is perinatally lethal when homozygous. Two dominant missense mutations of TMEM98, A193P and H196P, are associated with human nanophthalmos. In the mouse these mutations cause recessive retinal defects similar to the Rwhs phenotype, either alone or in combination with each other, but do not cause nanophthalmos. The retinal folds did not affect retinal function as assessed by electroretinography. Within the folds there was accumulation of disorganized outer segment material as demonstrated by immunohistochemistry and electron microscopy, and macrophages had infiltrated into these regions. // Conclusions: Mutations in the mouse orthologue of the human nanophthalmos gene TMEM98 do not result in small eyes. Rather, there is localized disruption of the laminar structure of the photoreceptors.

Type: Article
Title: Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse
Open access status: An open access version is available from UCL Discovery
DOI: 10.1167/iovs.18-25954
Publisher version: https://doi.org/10.1167/iovs.18-25954
Language: English
Additional information: Copyright © 2019 The Authors. This work is licensed under a Creative Commons Attribution 4.0 International License.
Keywords: nanophthalmos, mouse models, retina, genetic diseases
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10078095
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