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ResearchIn-Press PreviewGeneticsOphthalmology Open Access | 10.1172/jci.insight.194681

Splicing variants in MYRF cause partial loss-of-function in the retinal pigment epithelium leading to nanophthalmos

Gabrielle M. Rozumek,1 Michelle L. Brinkmeier,2 Bin Guan,3 Su Qing Wang,1 Catherine Tower,2 Nina T. Yang,1 Rachel S. Lim,1 Dejuan Kong,1 Daniel Soden,1 Qitao Zhang,1 John Y.S. Han,1 Jason M.L. Miller,1 Lijin Dong,3 D. Ford Hannum,1 Sayoko E. Moroi,4 Julia E. Richards,1 Robert B. Hufnagel,3 and Lev Prasov1

1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, United States of America

2Department of Human Genetics, University of Michigan, Ann Arbor, United States of America

3National Eye Institute, National Institutes of Health, Bethesda, United States of America

4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

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Published February 26, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.194681.
Copyright © 2026, Rozumek et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 26, 2026 - Version history
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Abstract

Improper light focus on the retina, refractive error, is primarily caused by eye size differences and is the leading cause of vision loss worldwide. C-terminal variants in the Myelin Regulatory Factor (MYRF) gene, a retinal pigment epithelium (RPE)-derived transcription factor, lead to isolated nanophthalmos characterized by a small, though structurally sound eye. However, other MYRF loss-of-function variants cause syndromic disease. To address this discrepancy, in vitro and animal studies were performed on a pathogenic C-terminal variant dG-MYRF (p.Gly1126fs30*, c.3376-1G>A). Human RPE-cells or primary RPE transduced with dG-MYRF showed reduced target gene expression, with decreased steady-state levels of the C-terminal cleavage product, but normal cleavage and localization. A homozygous humanized MYRF C-terminal mouse model (MyrfhumdG/humdG) was embryonic lethal by embryonic day (E) 18.5, while wildtype (MyrfhumWT/humWT) mice were viable. Single-cell RNA-seq from E17.5 MyrfhumdG/humdG and knockout RxCre;Myrffl/fl (E15.5 and P0) mice revealed shared differentially expressed genes, with decreased effect size in the MyrfhumdG/humdG eyes. These findings support dG-MYRF as a hypomorphic allele. Additionally, two MYRF splicing variants creating nonfunctional isoforms were found in families with isolated nanophthalmos. Overall, hypomorphic MYRF alleles underlie isolated nanophthalmos, supporting a tissue-specific threshold effect and highlighting unique roles for the MYRF C-terminus in the RPE.

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graphical abstract
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Version history
  • Version 1 (February 26, 2026): In-Press Preview
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