Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice.
Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-05-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1008130 |
| _version_ | 1797661460328873984 |
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| author | Sarah J Garnai Michelle L Brinkmeier Ben Emery Tomas S Aleman Louise C Pyle Biliana Veleva-Rotse Robert A Sisk Frank W Rozsa Ayse Bilge Ozel Jun Z Li Sayoko E Moroi Steven M Archer Cheng-Mao Lin Sarah Sheskey Laurel Wiinikka-Buesser James Eadie Jill E Urquhart Graeme C M Black Mohammad I Othman Michael Boehnke Scot A Sullivan Gregory L Skuta Hemant S Pawar Alexander E Katz Laryssa A Huryn Robert B Hufnagel Genomic Ascertainment Cohort Sally A Camper Julia E Richards Lev Prasov |
| author_facet | Sarah J Garnai Michelle L Brinkmeier Ben Emery Tomas S Aleman Louise C Pyle Biliana Veleva-Rotse Robert A Sisk Frank W Rozsa Ayse Bilge Ozel Jun Z Li Sayoko E Moroi Steven M Archer Cheng-Mao Lin Sarah Sheskey Laurel Wiinikka-Buesser James Eadie Jill E Urquhart Graeme C M Black Mohammad I Othman Michael Boehnke Scot A Sullivan Gregory L Skuta Hemant S Pawar Alexander E Katz Laryssa A Huryn Robert B Hufnagel Genomic Ascertainment Cohort Sally A Camper Julia E Richards Lev Prasov |
| author_sort | Sarah J Garnai |
| collection | DOAJ |
| description | Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development. |
| first_indexed | 2024-03-11T18:44:54Z |
| format | Article |
| id | doaj.art-94bbb35e2ae74ac4ade880700b4d20c2 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-03-11T18:44:54Z |
| publishDate | 2019-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-94bbb35e2ae74ac4ade880700b4d20c22023-10-12T05:31:13ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042019-05-01155e100813010.1371/journal.pgen.1008130Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice.Sarah J GarnaiMichelle L BrinkmeierBen EmeryTomas S AlemanLouise C PyleBiliana Veleva-RotseRobert A SiskFrank W RozsaAyse Bilge OzelJun Z LiSayoko E MoroiSteven M ArcherCheng-Mao LinSarah SheskeyLaurel Wiinikka-BuesserJames EadieJill E UrquhartGraeme C M BlackMohammad I OthmanMichael BoehnkeScot A SullivanGregory L SkutaHemant S PawarAlexander E KatzLaryssa A HurynRobert B HufnagelGenomic Ascertainment CohortSally A CamperJulia E RichardsLev PrasovNanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.https://doi.org/10.1371/journal.pgen.1008130 |
| spellingShingle | Sarah J Garnai Michelle L Brinkmeier Ben Emery Tomas S Aleman Louise C Pyle Biliana Veleva-Rotse Robert A Sisk Frank W Rozsa Ayse Bilge Ozel Jun Z Li Sayoko E Moroi Steven M Archer Cheng-Mao Lin Sarah Sheskey Laurel Wiinikka-Buesser James Eadie Jill E Urquhart Graeme C M Black Mohammad I Othman Michael Boehnke Scot A Sullivan Gregory L Skuta Hemant S Pawar Alexander E Katz Laryssa A Huryn Robert B Hufnagel Genomic Ascertainment Cohort Sally A Camper Julia E Richards Lev Prasov Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. PLoS Genetics |
| title | Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. |
| title_full | Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. |
| title_fullStr | Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. |
| title_full_unstemmed | Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. |
| title_short | Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. |
| title_sort | variants in myelin regulatory factor myrf cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice |
| url | https://doi.org/10.1371/journal.pgen.1008130 |
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