The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification

Abstract

<jats:title>Abstract</jats:title><jats:p>The precise control of eye size is essential for normal vision. <jats:italic>TMEM98</jats:italic> is a highly conserved and widely expressed gene which appears to be involved in eye size regulation. Mutations in human <jats:italic>TMEM98</jats:italic> are found in patients with nanophthalmos (very small eyes) and variants near the gene are associated in population studies with myopia and increased eye size. As complete loss of function mutations in mouse <jats:italic>Tmem98</jats:italic> result in perinatal lethality, we produced mice deficient for <jats:italic>Tmem98</jats:italic> in the retinal pigment epithelium (RPE), where <jats:italic>Tmem98</jats:italic> is highly expressed. These mice have greatly enlarged eyes that are very fragile with very thin retinas. To gain insight into the mechanism of action we used a proximity labelling approach to discover interacting proteins and identified MYRF as an interacting partner. Mutations of <jats:italic>MYRF</jats:italic> are also associated with nanophthalmos. The protein is an endoplasmic reticulum-tethered transcription factor which undergoes autoproteolytic cleavage to liberate the N-terminal part which then translocates to the nucleus where it acts as a transcription factor. We find that TMEM98 inhibits the self-cleavage of MYRF, in a novel regulatory mechanism. In RPE lacking TMEM98, MYRF is ectopically activated and abnormally localised to the nuclei.</jats:p><jats:sec><jats:title>Author summary</jats:title><jats:p>Having the correct eye size is important, too large and you will be short-sighted and too small and you will be far-sighted. Nanophthalmos, literally very small eye from the Greek, is a condition where the eye is very small but structurally normal. In addition to being farsighted such eyes are prone to glaucoma which can lead to loss of vision. Here we studied a protein called TMEM98 which is found in the membranes of the cells which form a layer at the back of eye called the retinal pigment epithelium (RPE). Mutations in <jats:italic>TMEM98</jats:italic> have been found in nanophthalmos patients. Patients have one normal copy of the gene and one carrying a mutation. We removed <jats:italic>Tmem98</jats:italic> from the RPE of mice in order to ascertain its function. We found, surprisingly, that rather than having small eyes this led to the development of very large eyes that were structurally fragile. We went to on to identify protein partners of TMEM98 and found that it interacts with a protein called MYRF, mutations in which also causes nanophthalmos. This work demonstrates the importance of <jats:italic>TMEM98</jats:italic> in eye size specification.</jats:p></jats:sec>