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.

doi:10.1371/journal.pgen.1008583

Cited by 18 publications

(15 citation statements)

References 58 publications

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“…Interestingly, all three identified missense variants in TMEM98 have involved proline substitution within helix 5 of the protein, which would be expected to alter the folding of this region of the protein. TMEM98 interacts with MYRF (another nanophthalmos gene product) in the retinal pigment epithelium (RPE) and oligodendrocytes in the brain 8 , 14 , 43 , though the interaction domain is dependent on the N-terminus of TMEM98 and not these C-terminal binding regions 44 . However, it is possible that a protein–protein interaction between TMEM98 and another protein leads to eye specific disease.…”

Section: Discussionmentioning

confidence: 99%

Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort

Prasov

Guan

Ullah

et al. 2020

Sci Rep

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Nanophthalmos is a rare condition defined by a small, structurally normal eye with resultant high hyperopia. While six genes have been implicated in this hereditary condition (MFRP, PRSS56, MYRF, TMEM98, CRB1,VMD2/BEST1), the relative contribution of these to nanophthalmos or to less severe high hyperopia (≥ + 5.50 spherical equivalent) has not been fully elucidated. We collected probands and families (n = 56) with high hyperopia or nanophthalmos (≤ 21.0 mm axial length). Of 53 families that passed quality control, plausible genetic diagnoses were identified in 10/53 (18.8%) by high-throughput panel or pooled exome sequencing. These include 1 TMEM98 family (1.9%), 5 MFRP families (9.4%), and 4 PRSS56 families (7.5%), with 4 additional families having single allelic hits in MFRP or PRSS56 (7.5%). A novel deleterious TMEM98 variant (NM_015544.3, c.602G>C, p.(Arg201Pro)) segregated with disease in 4 affected members of a family. Multiple novel missense and frameshift variants in MFRP and PRSS56 were identified. PRSS56 families were more likely to have choroidal folds than other solved families, while MFRP families were more likely to have retinal degeneration. Together, this study defines the prevalence of nanophthalmos gene variants in high hyperopia and nanophthalmos and indicates that a large fraction of cases remain outside of single gene coding sequences.

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Section: Discussionmentioning

confidence: 99%

Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort

Prasov

Guan

Ullah

et al. 2020

Sci Rep

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“…Notably, RNA-Seq analysis revealed that Prss56 and Adamts19 were the top two differentially expressed genes between Prss56 mutant ( Prss56 -/- ) and control ( Prss56 +/- ) retina. Besides Prss56 , Tmem98 was the only other differentially expressed gene that has previously been implicated in nanophthalmos [ 8 , 25 ] and was found to be significantly downregulated in the retina from Prss56 -/- mice compared to control Prss56 +/- mice ( S1 Table ). Interestingly, TMEM98 , which encodes a single transmembrane protein of unknown function, is also one of the several loci associated with high myopia in genome-wide association study (GWAS) [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, TMEM98 , which encodes a single transmembrane protein of unknown function, is also one of the several loci associated with high myopia in genome-wide association study (GWAS) [ 12 ]. Notably, conditional ablation of Tmem98 from the RPE, leads to significant increase in ocular size and axial length [ 8 ]. Thus, it is possible that the reduced Tmem98 expression detected in Prss56 -/- mice might have resulted from the differential expression in the fraction of RPE attached to the isolated retina for RNA-Seq analysis.…”

Section: Discussionmentioning

confidence: 99%

Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation

et al. 2021

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Precise regulation of ocular size is a critical determinant of normal visual acuity. Although it is generally accepted that ocular growth relies on a cascade of signaling events transmitted from the retina to the sclera, the factors and mechanism(s) involved are poorly understood. Recent studies have highlighted the importance of the retinal secreted serine protease PRSS56 and transmembrane glycoprotein MFRP, a factor predominantly expressed in the retinal pigment epithelium (RPE), in ocular size determination. Mutations in PRSS56 and MFRP constitute a major cause of nanophthalmos, a condition characterized by severe reduction in ocular axial length/extreme hyperopia. Interestingly, common variants of these genes have been implicated in myopia, a condition associated with ocular elongation. Consistent with these findings, mice with loss of function mutation in PRSS56 or MFRP exhibit a reduction in ocular axial length. However, the molecular network and cellular processes involved in PRSS56- and MFRP-mediated ocular axial growth remain elusive. Here, we show that Adamts19 expression is significantly upregulated in the retina of mice lacking either Prss56 or Mfrp. Importantly, using genetic mouse models, we demonstrate that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in Prss56 and Mfrp mutant mice. These results suggest that the upregulation of retinal Adamts19 is part of an adaptive molecular response to counteract impaired ocular growth. Using a complementary genetic approach, we show that loss of PRSS56 or MFRP function prevents excessive ocular axial growth in a mouse model of early-onset myopia caused by a null mutation in Irbp, thus, demonstrating that PRSS56 and MFRP are also required for pathological ocular elongation. Collectively, our findings provide new insights into the molecular network involved in ocular axial growth and support a role for molecular crosstalk between the retina and RPE involved in refractive development.

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“…Cross and colleagues did just that in a study published in April 2020's issue of PLOS Genetics [15]. The authors provide yet another surprising, but not unexpected finding, that mice lacking Tmem98 have greatly enlarged eyes with long axial length.…”

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confidence: 97%

Not too long, not too short: Goldilocks principle of eye size

Kuchtey

2020

PLoS Genet

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For most of the world, normal vision and visual acuity are central to our lives and livelihoods. Abnormal vision is often equated with conditions such as cataracts or retinal degeneration, but increasingly recognized contributors to abnormal vision are serious disturbances in visual acuity caused by uncorrected refractive error. In 2017, the Vision Loss Expert Group projected that uncorrected refractive error will become a major cause of global vision impairment and blindness by 2020 [1]. Although refractive error such as nearsightedness (myopia) and farsightedness (hyperopia) is usually correctable with eyeglasses, high myopia and high hyperopia can result in significant vision loss, and even irreversible blindness, due to complications such as macular degeneration and glaucoma. Myopic macular degeneration gives rise to similar outcomes as does age-related macular degeneration, with a notable difference-the former affects patients of much younger age. At the other end of the refractive spectrum, high hyperopia commonly leads to angle closure glaucoma. Furthermore, extremely high hyperopia associated with nanophthalmos-a small eye caused by developmental abnormalities-almost always leads to angle closure glaucoma, for which surgical correction is challenging and often associated with severe complications [2]. Understanding the pathogenesis of refractive error is greatly needed to develop effective treatments. High myopia or hyperopia is commonly caused by lengthening or shortening of axial length (AL) of the eye, respectively. If AL is too long, the sclera (the white outer layer of the eye) becomes stretched and thinned, predisposing to retinal detachment and degeneration of the retinal pigment epithelium. Conversely, if AL is too short, internal eye structures are crowded, and the sclera becomes thickened, predisposing to angle closure glaucoma and choroidal effusion. Recent studies in PLOS Genetics provide new insight into the genes and gene interactions, that contribute to abnormalities in axial length and refraction, and, furthermore, represent an intersection between common and rare genetic disease. On the common side of the spectrum, myopia and hyperopia have been the subject of several genome wide association studies (GWAS). TMEM98, which encodes a widely expressed single transmembrane protein of unknown function [3,4], is one of several loci associated with high myopia in GWAS, but a definitive and mechanistic role for TMEM98 in axial length has not been apparent from GWAS. On the rare side of the spectrum, however, deleterious coding alterations in TMEM98 co-segregate with autosomal dominant nanophthalmos in large multigenerational families [5,6]. Intriguingly, nanophthalmos is the phenotypic opposite of high myopia, a paradox that is underscored by a report of 3 variants in TMEM98 associated with high myopia in Chinese patients [7].

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

Cited by 18 publications

References 58 publications

Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort

Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort

Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation

Not too long, not too short: Goldilocks principle of eye size

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