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) |
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Article number | e1008130 |
Journal | PLoS genetics |
Volume | 15 |
Issue number | 5 |
DOIs | |
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