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

摘要

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 summary Hyperopia or farsightedness is a common condition that can cause visual impairment especially in children. The extreme of this condition is called nanophthalmos, a small crowded eye in which inappropriate drainage of aqueous humor from the eye can lead to glaucoma and vision loss. We previously described a large family with inherited nanophthalmos, but the genetic defect that segregated in this family was unknown. Here, we have used a new approach combining linkage analysis and pooled sequencing to identify the genetic cause in this family. We identified a splice site mutation that causes the myelin regulatory factor ( MYRF ) gene to produce an aberrant protein. Additionally, a child with syndromic manifestations and a deleterious MYRF variant shared the same eye condition. Using a mouse model in which MYRF is absent from eye tissue during early development, we established a role for this transcription factor in the development of the retinal pigment epithelium and retina. We showed that MYRF interacts with and regulates expression of another membrane protein, TMEM98, which has been implicated in nanophthalmos. Our study establishes MYRF as a new disease gene for nanophthalmos and a regulator of eye development.