Cargando…

Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse

Nanophthalmos is characterised by shorter posterior and anterior segments of the eye, with a predisposition towards high hyperopia and primary angle-closure glaucoma. Variants in TMEM98 have been associated with autosomal dominant nanophthalmos in multiple kindreds, but definitive evidence for causa...

Descripción completa

Detalles Bibliográficos
Autores principales: Hassall, Mark M., Javadiyan, Shari, Klebe, Sonja, Awadalla, Mona S., Sharma, Shiwani, Qassim, Ayub, White, Melissa, Thomas, Paul Q., Craig, Jamie E., Siggs, Owen M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10328987/
https://www.ncbi.nlm.nih.gov/pubmed/37419942
http://dx.doi.org/10.1038/s41598-023-37855-x
_version_ 1785069925880037376
author Hassall, Mark M.
Javadiyan, Shari
Klebe, Sonja
Awadalla, Mona S.
Sharma, Shiwani
Qassim, Ayub
White, Melissa
Thomas, Paul Q.
Craig, Jamie E.
Siggs, Owen M.
author_facet Hassall, Mark M.
Javadiyan, Shari
Klebe, Sonja
Awadalla, Mona S.
Sharma, Shiwani
Qassim, Ayub
White, Melissa
Thomas, Paul Q.
Craig, Jamie E.
Siggs, Owen M.
author_sort Hassall, Mark M.
collection PubMed
description Nanophthalmos is characterised by shorter posterior and anterior segments of the eye, with a predisposition towards high hyperopia and primary angle-closure glaucoma. Variants in TMEM98 have been associated with autosomal dominant nanophthalmos in multiple kindreds, but definitive evidence for causation has been limited. Here we used CRISPR/Cas9 mutagenesis to recreate the human nanophthalmos-associated TMEM98 p.(Ala193Pro) variant in mice. The p.(Ala193Pro) variant was associated with ocular phenotypes in both mice and humans, with dominant inheritance in humans and recessive inheritance in mice. Unlike their human counterparts, p.(Ala193Pro) homozygous mutant mice had normal axial length, normal intraocular pressure, and structurally normal scleral collagen. However, in both homozygous mice and heterozygous humans, the p.(Ala193Pro) variant was associated with discrete white spots throughout the retinal fundus, with corresponding retinal folds on histology. This direct comparison of a TMEM98 variant in mouse and human suggests that certain nanophthalmos-associated phenotypes are not only a consequence of a smaller eye, but that TMEM98 may itself play a primary role in retinal and scleral structure and integrity.
format Online
Article
Text
id pubmed-10328987
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-103289872023-07-09 Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse Hassall, Mark M. Javadiyan, Shari Klebe, Sonja Awadalla, Mona S. Sharma, Shiwani Qassim, Ayub White, Melissa Thomas, Paul Q. Craig, Jamie E. Siggs, Owen M. Sci Rep Article Nanophthalmos is characterised by shorter posterior and anterior segments of the eye, with a predisposition towards high hyperopia and primary angle-closure glaucoma. Variants in TMEM98 have been associated with autosomal dominant nanophthalmos in multiple kindreds, but definitive evidence for causation has been limited. Here we used CRISPR/Cas9 mutagenesis to recreate the human nanophthalmos-associated TMEM98 p.(Ala193Pro) variant in mice. The p.(Ala193Pro) variant was associated with ocular phenotypes in both mice and humans, with dominant inheritance in humans and recessive inheritance in mice. Unlike their human counterparts, p.(Ala193Pro) homozygous mutant mice had normal axial length, normal intraocular pressure, and structurally normal scleral collagen. However, in both homozygous mice and heterozygous humans, the p.(Ala193Pro) variant was associated with discrete white spots throughout the retinal fundus, with corresponding retinal folds on histology. This direct comparison of a TMEM98 variant in mouse and human suggests that certain nanophthalmos-associated phenotypes are not only a consequence of a smaller eye, but that TMEM98 may itself play a primary role in retinal and scleral structure and integrity. Nature Publishing Group UK 2023-07-07 /pmc/articles/PMC10328987/ /pubmed/37419942 http://dx.doi.org/10.1038/s41598-023-37855-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hassall, Mark M.
Javadiyan, Shari
Klebe, Sonja
Awadalla, Mona S.
Sharma, Shiwani
Qassim, Ayub
White, Melissa
Thomas, Paul Q.
Craig, Jamie E.
Siggs, Owen M.
Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse
title Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse
title_full Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse
title_fullStr Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse
title_full_unstemmed Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse
title_short Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse
title_sort phenotypic consequences of a nanophthalmos-associated tmem98 variant in human and mouse
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10328987/
https://www.ncbi.nlm.nih.gov/pubmed/37419942
http://dx.doi.org/10.1038/s41598-023-37855-x
work_keys_str_mv AT hassallmarkm phenotypicconsequencesofananophthalmosassociatedtmem98variantinhumanandmouse
AT javadiyanshari phenotypicconsequencesofananophthalmosassociatedtmem98variantinhumanandmouse
AT klebesonja phenotypicconsequencesofananophthalmosassociatedtmem98variantinhumanandmouse
AT awadallamonas phenotypicconsequencesofananophthalmosassociatedtmem98variantinhumanandmouse
AT sharmashiwani phenotypicconsequencesofananophthalmosassociatedtmem98variantinhumanandmouse
AT qassimayub phenotypicconsequencesofananophthalmosassociatedtmem98variantinhumanandmouse
AT whitemelissa phenotypicconsequencesofananophthalmosassociatedtmem98variantinhumanandmouse
AT thomaspaulq phenotypicconsequencesofananophthalmosassociatedtmem98variantinhumanandmouse
AT craigjamiee phenotypicconsequencesofananophthalmosassociatedtmem98variantinhumanandmouse
AT siggsowenm phenotypicconsequencesofananophthalmosassociatedtmem98variantinhumanandmouse