Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice

The Genomic Ascertainment Cohort

doi:10.1371/journal.pgen.1008130

Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice

The Genomic Ascertainment Cohort

Ophthalmology

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

Abstract

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.

Original language	English (US)
Article number	e1008130
Journal	PLoS genetics
Volume	15
Issue number	5
DOIs	https://doi.org/10.1371/journal.pgen.1008130
State	Published - May 2019

Funding

L.P. was supported by the Knights Templar Eye Foundation Career Starter Award, the Alliance for Vision Research Award, and the Michigan Ophthalmology Trainee Career Development Award. C.M.L. and S.S. were supported by the National Eye Institute Vision Core Grant P30 EY007003 (University of Michigan). J.E. R. was supported by National Eye Institute grants EY09580 and EY11671, by the Research to Prevent Blindness unrestricted grant to the W.K. Kellogg Eye Center/University of Michigan, and by the Midwest Eye Bank. B.E. was supported by the National Multiple Sclerosis Society grant RG 5106A1, the Warren Endowed professorship in Neuroscience Research, and Race to Erase MS. L. C.P. was supported by a grant from the National Center for Advancing Translational Sciences KL2-TR000187903. R.B.H, L.A.H, and L.P. were also supported by National Eye Institute Intramural Funds. TGAC and A.E.K. were supported by the National Institutes of Health Director Challenge Fund. G.C.M.B. was supported by Retina UK/RP Fighting Blindness and Fight for Sight (RP Genome Project GR586) and by the NIHR Manchester BRC. G.L.S. was supported by Research to Prevent Blindness Unrestricted Grant to Dean McGee Eye Institute/University of Oklahoma. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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10.1371/journal.pgen.1008130

Cite this

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title = "Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice",

abstract = "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.",

author = "{The Genomic Ascertainment Cohort} and Garnai, {Sarah J.} and Brinkmeier, {Michelle L.} and Ben Emery and Aleman, {Tomas S.} and Pyle, {Louise C.} and Biliana Veleva-Rotse and Sisk, {Robert A.} and Rozsa, {Frank W.} and Ozel, {Ayse Bilge} and Li, {Jun Z.} and Moroi, {Sayoko E.} and Archer, {Steven M.} and Lin, {Cheng Mao} and Sarah Sheskey and Laurel Wiinikka-Buesser and James Eadie and Urquhart, {Jill E.} and Black, {Graeme C.M.} and Othman, {Mohammad I.} and Michael Boehnke and Sullivan, {Scot A.} and Skuta, {Gregory L.} and Pawar, {Hemant S.} and Katz, {Alexander E.} and Huryn, {Laryssa A.} and Hufnagel, {Robert B.} and Camper, {Sally A.} and Richards, {Julia E.} and Lev Prasov and Cagri Besirli and Brenda Bohnsack and Monte, {Monte Del} and Susan Elner and Thiran Jayasundera and Johnson, {Mark W.} and Shivani Kamat and Jasmine Serpen and Katie Lewis and Priscilla Chan and Jennifer Johnston and Tyra Wolfsberg and Justin Paschall and Les Biesecker and Bob Lyons and Susan Dagenais and Michael Wegener",

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AU - Emery, Ben

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AU - Pyle, Louise C.

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AU - Sisk, Robert A.

AU - Rozsa, Frank W.

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AU - Li, Jun Z.

AU - Moroi, Sayoko E.

AU - Archer, Steven M.

AU - Lin, Cheng Mao

AU - Sheskey, Sarah

AU - Wiinikka-Buesser, Laurel

AU - Eadie, James

AU - Urquhart, Jill E.

AU - Black, Graeme C.M.

AU - Othman, Mohammad I.

AU - Boehnke, Michael

AU - Sullivan, Scot A.

AU - Skuta, Gregory L.

AU - Pawar, Hemant S.

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AU - Huryn, Laryssa A.

AU - Hufnagel, Robert B.

AU - Camper, Sally A.

AU - Richards, Julia E.

AU - Prasov, Lev

AU - Besirli, Cagri

AU - Bohnsack, Brenda

AU - Monte, Monte Del

AU - Elner, Susan

AU - Jayasundera, Thiran

AU - Johnson, Mark W.

AU - Kamat, Shivani

AU - Serpen, Jasmine

AU - Lewis, Katie

AU - Chan, Priscilla

AU - Johnston, Jennifer

AU - Wolfsberg, Tyra

AU - Paschall, Justin

AU - Biesecker, Les

AU - Lyons, Bob

AU - Dagenais, Susan

AU - Wegener, Michael

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Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice

Abstract

Funding

ASJC Scopus subject areas

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