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

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dc.contributor.authorHassall, M.M.
dc.contributor.authorJavadiyan, S.
dc.contributor.authorKlebe, S.
dc.contributor.authorAwadalla, M.S.
dc.contributor.authorSharma, S.
dc.contributor.authorQassim, A.
dc.contributor.authorWhite, M.
dc.contributor.authorThomas, P.Q.
dc.contributor.authorCraig, J.E.
dc.contributor.authorSiggs, O.M.
dc.date.issued2023
dc.descriptionPublished online: 07 July 2023
dc.description.abstractNanophthalmos 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.
dc.description.statementofresponsibilityMark M. Hassall, Shari Javadiyan, Sonja Klebe, Mona S. Awadalla, Shiwani Sharma, Ayub Qassim, Melissa White, Paul Q. Thomas, Jamie E. Craig and Owen M. Siggs
dc.identifier.citationScientific Reports, 2023; 13(1):11017-1-11017-7
dc.identifier.doi10.1038/s41598-023-37855-x
dc.identifier.issn2045-2322
dc.identifier.issn2045-2322
dc.identifier.orcidHassall, M.M. [0000-0002-6180-7954]
dc.identifier.orcidWhite, M. [0000-0002-8748-9210]
dc.identifier.urihttps://hdl.handle.net/2440/139119
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1116360
dc.rights© The Author(s) 2023. 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/.
dc.source.urihttps://doi.org/10.1038/s41598-023-37855-x
dc.subjectFundus Oculi
dc.subject.meshFundus Oculi
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshMicrophthalmos
dc.subject.meshGlaucoma, Angle-Closure
dc.subject.meshHyperopia
dc.subject.meshMembrane Proteins
dc.subject.meshPhenotype
dc.titlePhenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse
dc.typeJournal article
pubs.publication-statusPublished

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