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  1. Artikel ; Online: The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification.

    Cross, Sally H / Mckie, Lisa / Hurd, Toby W / Riley, Sam / Wills, Jimi / Barnard, Alun R / Young, Fiona / MacLaren, Robert E / Jackson, Ian J

    PLoS genetics

    2020  Band 16, Heft 4, Seite(n) e1008583

    Abstract: 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 ... ...

    Abstract 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.
    Mesh-Begriff(e) Animals ; Electroretinography ; Eye/anatomy & histology ; Eye/metabolism ; Eye Abnormalities/genetics ; Female ; Gene Deletion ; Loss of Function Mutation ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Knockout ; Organ Size/genetics ; Protein Binding ; Protein Transport ; Retinal Pigment Epithelium/abnormalities ; Retinal Pigment Epithelium/metabolism ; Retinaldehyde/metabolism ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/chemistry ; Transcription Factors/metabolism
    Chemische Substanzen Membrane Proteins ; Tmem98 protein, mouse ; Transcription Factors ; myelin gene regulatory factor, mouse ; Retinaldehyde (RR725D715M)
    Sprache Englisch
    Erscheinungsdatum 2020-04-01
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1008583
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse.

    Cross, Sally H / Mckie, Lisa / Keighren, Margaret / West, Katrine / Thaung, Caroline / Davey, Tracey / Soares, Dinesh C / Sanchez-Pulido, Luis / Jackson, Ian J

    Investigative ophthalmology & visual science

    2019  Band 60, Heft 8, Seite(n) 2875–2887

    Abstract: 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 modeled these ... ...

    Abstract 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 modeled these mutations in mice and characterized 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 disorganized 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.
    Mesh-Begriff(e) Animals ; Axial Length, Eye/pathology ; CRISPR-Cas Systems ; Electroretinography ; Female ; Gene Expression Regulation/physiology ; Humans ; Immunohistochemistry ; Male ; Membrane Proteins/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microphthalmos/genetics ; Microphthalmos/pathology ; Microscopy, Electron, Transmission ; Mutation, Missense ; Ophthalmoscopy ; Photoreceptor Cells, Vertebrate/pathology ; Polymerase Chain Reaction ; Retinal Diseases/genetics ; Retinal Diseases/pathology
    Chemische Substanzen Membrane Proteins ; TMEM98 protein, human
    Sprache Englisch
    Erscheinungsdatum 2019-06-30
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 391794-0
    ISSN 1552-5783 ; 0146-0404
    ISSN (online) 1552-5783
    ISSN 0146-0404
    DOI 10.1167/iovs.18-25954
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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