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


Autoři: Sally H. Cross aff001;  Lisa Mckie aff001;  Toby W. Hurd aff001;  Sam Riley aff001;  Jimi Wills aff001;  Alun R. Barnard aff002;  Fiona Young aff003;  Robert E. MacLaren aff002;  Ian J. Jackson aff001
Působiště autorů: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom aff001;  Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, The John Radcliffe Hospital, Oxford, United Kingdom aff002;  Electron Microscopy, Pathology, Western General Hospital, Edinburgh, United Kingdom aff003;  Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, United Kingdom aff004
Vyšlo v časopise: The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008583
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008583

Souhrn

The precise control of eye size is essential for normal vision. TMEM98 is a highly conserved and widely expressed gene which appears to be involved in eye size regulation. Mutations in human TMEM98 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 Tmem98 result in perinatal lethality, we produced mice deficient for Tmem98 in the retinal pigment epithelium (RPE), where Tmem98 is highly expressed. These mice have greatly enlarged eyes that are very fragile with very thin retinas, compressed choroid and thin sclera. 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 MYRF 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. Our findings highlight the importance of the interplay between TMEM98 and MYRF in determining the size of the eye.

Klíčová slova:

Cell signaling – Cell staining – Cornea – Eyes – Immunostaining – Missense mutation – Retina – Transcription factors


Zdroje

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