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

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Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse Genetics Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse Sally H. Cross,1 Lisa Mckie,1 Margaret Keighren,1 Katrine West,1 Caroline Thaung,2,3 Tracey Davey,4 Dinesh C. Soares,*,1 Luis Sanchez-Pulido,1 and Ian J. Jackson1 1MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom 2Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom 3University College London Institute of Ophthalmology, London, United Kingdom 4Electron Microscopy Research Services, Newcastle University, Newcastle, United Kingdom Correspondence: Sally H. Cross, PURPOSE. We previously found a dominant mutation, Rwhs, causing white spots on the retina MRC Human Genetics Unit, MRC accompanied by retinal folds. Here we identify the mutant gene to be Tmem98. In humans, Institute of Genetics and Molecular mutations in the orthologous gene cause nanophthalmos. We modeled these mutations in Medicine, University of Edinburgh, mice and characterized the mutant eye phenotypes of these and Rwhs. Crewe Road, Edinburgh EH4 2XU, UK; METHODS. The Rwhs mutation was identified to be a missense mutation in Tmem98 by genetic [email protected]. mapping and sequencing. The human TMEM98 nanophthalmos missense mutations were Current affiliation: *ACS International made in the mouse gene by CRISPR-Cas9. Eyes were examined by indirect ophthalmoscopy Ltd., Oxford, United Kingdom and the retinas imaged using a retinal camera. Electroretinography was used to study retinal function. Histology, immunohistochemistry, and electron microscopy techniques were used Submitted: October 10, 2018 Accepted: May 28, 2019 to study adult eyes. Citation: Cross SH, Mckie L, Keighren RESULTS. An I135T mutation of Tmem98 causes the dominant Rwhs phenotype and is M, et al. Missense mutations in the perinatally lethal when homozygous. Two dominant missense mutations of TMEM98, A193P human nanophthalmos gene TMEM98 and H196P, are associated with human nanophthalmos. In the mouse these mutations cause cause retinal defects in the mouse. recessive retinal defects similar to the Rwhs phenotype, either alone or in combination with Invest Ophthalmol Vis Sci. each other, but do not cause nanophthalmos. The retinal folds did not affect retinal function 2019;60:2875–2887. https://doi.org/ as assessed by electroretinography. Within the folds there was accumulation of disorganized 10.1167/iovs.18-25954 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. Keywords: nanophthalmos, mouse models, retina, genetic diseases here are a range of genetic disorders that present with a ascribed to a relative overgrowth of neural retina within a T reduced eye size. In microphthalmia the reduced size is smaller globe, resulting in folding of the excess retinal tissue. often associated with additional developmental eye defects, A number of genes have been found to be associated with such as coloboma, and may also include developmental defects nanophthalmos.2 Mutations in three genes have established in other organs. In some cases there is an overall size reduction associations with nanophthalmos. Several families with nano- without other developmental defects. The smaller eye may be a phthalmos have been found to have clear loss-of-function result of a reduction in size of the anterior segment alone mutations in both alleles of the gene encoding membrane-type (anterior microphthalmos), the posterior segment alone frizzled related protein, MFRP, that is expressed principally in (posterior microphthalmos), or a reduction of both. This last the retinal pigment epithelium (RPE) and ciliary body.3 category includes simple microphthalmos and the more severe Homozygous loss-of-function mutations in MFRP have been nanophthalmos.1,2 Posterior microphthalmos is sometimes found in other individuals with posterior microphthalmia plus considered as part of a continuum with nanophthalmos, as retinitis pigmentosa, foveoschisis, and drusen, indicating likely they have pathological and genetic features in common. In genetic background effects on the severity or range of the nanophthalmos eye length is reduced by 30% or more, and is disease.4–6 A second autosomal recessive nanophthalmos gene usually associated with other ocular features, notably a is PRSS56, encoding a serine protease. Families with biallelic thickened choroid and sclera, as well as a high incidence of mutations in this gene have been characterized, some of whom glaucoma, corneal defects, vascular defects, and a range of have posterior microphthalmia while others have nanophthal- retinal features including retinitis pigmentosa, retinoschisis, mos.7–9 There is no apparent genotype–phenotype correlation; retinal detachments, and retinal folds. Retinal folds are also there are patients with homozygous frameshift mutations with observed in posterior microphthalmos, and are sometimes either condition. Intriguingly, association of variants at PRSS56 Copyright 2019 The Authors iovs.arvojournals.org j ISSN: 1552-5783 2875 This work is licensed under a Creative Commons Attribution 4.0 International License. Downloaded from iovs.arvojournals.org on 07/18/2019 Human TMEM98 Nanophthalmos Mutations in the Mouse IOVS j July 2019 j Vol. 60 j No. 8 j 2876 with myopia has been reported in genome-wide association engineered to carry a missense mutation, Crb1C249W, that studies.10,11 causes retinitis pigmentosa in humans, although the OLM Most recently three families have been characterized in appears intact, retinal degeneration still occurs, albeit later which heterozygous mutations in TMEM98 are segregating than in the other models.31 Similarly to the human phenotype, with nanophthalmos. Two families have missense mutations; the extent of the retinal spotting observed in Crb1 mutants is the third has a 34-bp (base pair) deletion that removes the last strongly affected by the genetic background. 28 bases of exon 4 and the first 6 bases of intron 4 including Two lines of mice with spontaneous mutations in Mfrp have the splice donor site.12,13 The effect of the deletion on the been described.32–34 These do not recapitulate the nano- TMEM98 transcript is unknown, but in silico splicing phthalmic phenotype observed in humans. Instead, both have prediction programs (Alamut Visual Splicing Predictions) the same recessive phenotype of white spots on the retina, predict that it could result in exon 4 being skipped and the which correlate with abnormal cells below the retina that stain production of a potentially functional protein with an internal with macrophage markers, and progress to photoreceptor deletion. Alternatively, other splice defects would result in degeneration. For the Mfrprdx mutation, atrophy of the RPE frameshifts, nonsense-mediated decay, and loss of protein from was reported,33 and for Mfrprd6 a modest ocular axial length this allele. In this case the cause of the disease would be reduction from approximately 2.87 to 2.83 mm was reported haploinsufficiency. Caution in assigning a role for TMEM98 in although apparently not statistically significant.35 A screen for nanophthalmos has been raised by findings in another study in mice with increased intraocular pressure (IOP) found a splice which different heterozygous missense mutations in TMEM98 mutation in the Prss56 gene predicted to produce a truncated were found in patients with high myopia and cone-rod protein.8 The increased IOP was associated with a narrow or 14 dystrophy. closed iridocorneal angle, analogous to that seen in human Patients with heterozygous or homozygous mutations in the angle closure glaucoma. In addition these mice have eyes that 15 BEST1 gene can have a range of defects. BEST1 encodes the are smaller than in littermates, although the size reduction is bestrophin-1 protein, a transmembrane protein located in the variable and slight, ranging from a 0% to 10% decrease in axial 16 basolateral membrane of the RPE. The predominant disease length. Reduction in axial length becomes statistically signif- resulting from heterozygous mutations in BEST1 is Best icant only after postnatal day 7. More recently it has been vitelliform macular dystrophy, in which subretinal lipofuscin shown that mice deficient for have eyes with a 17 Prss56 deposits precede vision defects. These patients in early decreased axial length and hyperopia.36 stages have a normal electroretinogram (ERG) but have a defect In summary, the human nanophthalmos mutations modeled in electrooculography (EOG) indicative of an abnormality in in mice produce either a much less severe, or nonsignificant, the RPE. This can progress to retinitis pigmentosa. Five families axial length reduction (Prss56, Mfrp) or no effect on eye size have been reported with dominant vitreoretinochoroidopathy (Best1, Crb1). There are differences in the development of and nanophthalmos due to three different missense mutations human and mouse eyes, which probably underlies the in BEST1. Each mutant allele can produce two isoforms, one differences in mutant phenotype. containing a missense mutation and one containing an in-frame 18 To date no mouse models of TMEM98 have been reported. deletion. On the other hand, homozygous null mutations of We describe here characterization of
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