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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.

SUBMITTER: Garnai SJ

PROVIDER: S-EPMC6527243 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Garnai Sarah J SJ Brinkmeier Michelle L ML Emery Ben B Aleman Tomas S TS Pyle Louise C LC Veleva-Rotse Biliana B Sisk Robert A RA Rozsa Frank W FW Ozel Ayse Bilge AB Li Jun Z JZ Moroi Sayoko E SE Archer Steven M SM Lin Cheng-Mao CM Sheskey Sarah S Wiinikka-Buesser Laurel L Eadie James J Urquhart Jill E JE Black Graeme C M GCM Othman Mohammad I MI Boehnke Michael M Sullivan Scot A SA Skuta Gregory L GL Pawar Hemant S HS Katz Alexander E AE Huryn Laryssa A LA Hufnagel Robert B RB Camper Sally A SA Richards Julia E JE Prasov Lev L

PLoS genetics 20190502 5

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 ...[more]

PMID: 31048900

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Project description:PurposeAutosomal dominant nanophthalmos is an inherited eye disorder characterized by a structurally normal but smaller eye. Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications. In this study, the clinical features and the genetic basis of nanophthalmos were investigated in two large autosomal dominant nanophthalmos pedigrees.MethodsFourteen members of a Caucasian pedigree from the United States and 15 members of a pedigree from the Mariana Islands enrolled in a genetic study of nanophthalmos and contributed DNA samples. Twenty of 29 family members underwent eye examinations that included measurement of axial eye length and/or refractive error. The genetic basis of nanophthalmos in the pedigrees was studied with linkage analysis, whole exome sequencing, and candidate gene (i.e., TMEM98) sequencing to identify the nanophthalmos-causing gene.ResultsNine members of the pedigree from the United States and 11 members of the pedigree from the Mariana Islands were diagnosed with nanophthalmos that is transmitted as an autosomal dominant trait. The patients with nanophthalmos had abnormally short axial eye lengths, which ranged from 15.9 to 18.4 mm. Linkage analysis of the nanophthalmos pedigree from the United States identified nine large regions of the genome (greater than 10 Mbp) that were coinherited with disease in this family. Genes within these "linked regions" were examined for disease-causing mutations using exome sequencing, and a His196Pro mutation was detected in the TMEM98 gene, which was recently reported to be a nanophthalmos gene. Sanger sequencing subsequently showed that all other members of this pedigree with nanophthalmos also carry the His196Pro TMEM98 mutation. Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members. Neither TMEM98 mutation was detected in public exome sequence databases.ConclusionsA recent report identified a single TMEM98 missense mutation in a nanophthalmos pedigree. Our discovery of two additional TMEM98 mutations confirms the important role of the gene in the pathogenesis of autosomal dominant nanophthalmos.

Dataset Information

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

Publications

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

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