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.
Rozumek et al. (Thu,) studied this question.