Title

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

Authors

Sarah J. Garnai, University of Michigan W.K. Kellogg Eye Center
Michelle L. Brinkmeier, University of Michigan W.K. Kellogg Eye Center
Ben Emery, Oregon Health & Science University
Tomas S. Aleman, The Children's Hospital of Philadelphia
Louise C. Pyle, The Children's Hospital of Philadelphia
Biliana Veleva-Rotse, Oregon Health & Science University
Robert A. Sisk, Cincinnati Eye Institute
Frank W. Rozsa, University of Michigan W.K. Kellogg Eye Center
Ayse Bilge Ozel, University of Michigan, Ann Arbor
Jun Z. Li, University of Michigan, Ann Arbor
Sayoko E. Moroi, University of Michigan W.K. Kellogg Eye Center
Steven M. Archer, University of Michigan W.K. Kellogg Eye Center
Cheng Mao Lin, University of Michigan W.K. Kellogg Eye Center
Sarah Sheskey, University of Michigan W.K. Kellogg Eye Center
Laurel Wiinikka-Buesser, University of Michigan W.K. Kellogg Eye Center
James Eadie, University of Michigan W.K. Kellogg Eye Center
Jill E. Urquhart, Manchester University NHS Foundation Trust
Graeme C.M. Black, Manchester University NHS Foundation Trust
Mohammad I. Othman, University of Michigan W.K. Kellogg Eye Center
Michael Boehnke, University of Michigan, Ann Arbor
Scot A. Sullivan, Dean A. McGee Eye Institute
Gregory L. Skuta, Dean A. McGee Eye Institute
Hemant S. Pawar, University of Michigan W.K. Kellogg Eye Center
Alexander E. Katz, National Human Genome Research Institute (NHGRI)
Laryssa A. Huryn, National Eye Institute (NEI)
Robert B. Hufnagel, National Eye Institute (NEI)
Sally A. Camper, University of Michigan, Ann Arbor
Julia E. Richards, University of Michigan W.K. Kellogg Eye Center
Lev Prasov, University of Michigan W.K. Kellogg Eye Center
Cagri Besirli
Brenda Bohnsack
Monte Del Monte

Document Type

Journal Article

Publication Date

5-1-2019

Journal

PLoS Genetics

Volume

15

DOI

10.1371/journal.pgen.1008130

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.

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