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

Autor: Garnai SJ; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America.; Harvard Medical School, Boston, MA, United States of America., Brinkmeier ML; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America.; Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States of America., Emery B; Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science University, Portland, OR, United States of America., Aleman TS; The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.; Scheie Eye Institute, Department of Ophthalmology, Philadelphia, PA, United States of America., Pyle LC; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America., Veleva-Rotse B; Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science University, Portland, OR, United States of America., Sisk RA; Cincinnati Eye Institute, Cincinnati, Ohio, United States of America., Rozsa FW; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America.; Molecular and Behavior Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States of America., Ozel AB; Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States of America., Li JZ; Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States of America., Moroi SE; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America., Archer SM; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America., Lin CM; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America., Sheskey S; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America., Wiinikka-Buesser L; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America., Eadie J; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America., Urquhart JE; Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, St Mary's Hospital, Manchester, United Kingdom.; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom., Black GCM; Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, St Mary's Hospital, Manchester, United Kingdom.; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom., Othman MI; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America., Boehnke M; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States of America., Sullivan SA; Dean McGee Eye Institute, Department of Ophthalmology, University of Oklahoma, Oklahoma City, OK., Skuta GL; Dean McGee Eye Institute, Department of Ophthalmology, University of Oklahoma, Oklahoma City, OK., Pawar HS; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America., Katz AE; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States of America., Huryn LA; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, United States of America., Hufnagel RB; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, United States of America., Camper SA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States of America., Richards JE; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America.; Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States of America., Prasov L; Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States of America.; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2019 May 02; Vol. 15 (5), pp. e1008130. Date of Electronic Publication: 2019 May 02 (Print Publication: 2019).
DOI: 10.1371/journal.pgen.1008130
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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