RT Journal Article SR Electronic T1 Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse JF bioRxiv FD Cold Spring Harbor Laboratory SP 513846 DO 10.1101/513846 A1 Sally H. Cross A1 Lisa Mckie A1 Margaret Keighren A1 Katrine West A1 Caroline Thaung A1 Tracey Davey A1 Dinesh C. Soares A1 Luis Sanchez-Pulido A1 Ian J. Jackson YR 2019 UL http://biorxiv.org/content/early/2019/03/23/513846.abstract AB 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 modelled these mutations in mice and characterised 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 disorganised 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 localised disruption of the laminar structure of the photoreceptors.