{"doi":"10.1101/2025.04.21.649840","title":"Splicing variants in MYRF cause partial loss of function in the retinal pigment epithelium","abstract":"ABSTRACT Myelin Regulatory Factor (MYRF) regulates retinal pigment epithelial (RPE) development and variants in the C-terminus are linked to isolated nanophthalmos, while loss-of-function variants cause syndromic disease. To define the molecular mechanism of this discrepancy, in vitro and animal studies were performed on a pathogenic C-terminal variant (p.Gly1126fs30* or dG-MYRF). ARPE-19 cells transduced with dG-MYRF revealed reduced target gene expression compared to WT-MYRF, with reduced steady state levels of C-terminal MYRF cleavage product, but intact cleavage and localization. A homozygous humanized MYRF C-terminal ( Myrf humdG/humdG ) mouse model was embryonic lethal by embryonic day (E) 18.5, while humanized wildtype ( Myrf humWT/humWT ) showed normal expression and survival. Bioinformatic analysis on integrated single cell RNA-seq from humanized E17.5 and knockout Rx-Cre;Myrf fl/fl (E15.5 and P0) mice supported shared differentially expressed genes with decreased effect size in Myrf humdG/humdG eyes. These findings, and the viability differences, support that dG-MYRF is a hypomorphic allele. Further, two novel MYRF splicing variants were identified in families with isolated nanophthalmos, with one confirmed to alter 40% of spliced transcripts, creating a nonfunctional isoform. These cases corroborate that isolated nanophthalmos results from hypomorphic alleles of MYRF, supporting a tissue-specific threshold effect and suggests that the C-terminus has unique roles in the RPE.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557647,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":400273,"name":"Michelle L. Brinkmeier","orcid":"0000-0001-9505-4682","position":1,"is_corresponding":false},{"id":331821,"name":"Bin Guan","orcid":"0000-0001-5986-5189","position":2,"is_corresponding":false},{"id":1458147,"name":"Su Qing Wang","orcid":null,"position":3,"is_corresponding":false},{"id":502949,"name":"Catherine A. Tower","orcid":"0000-0003-4470-6227","position":4,"is_corresponding":false},{"id":1328976,"name":"Nina T. Yang","orcid":null,"position":5,"is_corresponding":false},{"id":1457783,"name":"Rachel Lim","orcid":"0000-0003-2833-3256","position":6,"is_corresponding":false},{"id":286497,"name":"Lijin Dong","orcid":"0000-0001-7401-9511","position":7,"is_corresponding":false},{"id":472719,"name":"D. Ford Hannum","orcid":"0000-0003-2998-9396","position":8,"is_corresponding":false},{"id":6877,"name":"Sayoko E. Moroi","orcid":"0000-0002-0418-0657","position":9,"is_corresponding":false},{"id":6893,"name":"Julia E. Richards","orcid":"0000-0003-4808-5931","position":10,"is_corresponding":false},{"id":103390,"name":"Robert B. Hufnagel","orcid":"0000-0003-3015-3545","position":11,"is_corresponding":false},{"id":434522,"name":"Lev Prasov","orcid":"0000-0002-6635-1116","position":12,"is_corresponding":false},{"id":1457782,"name":"Gabrielle M. Rozumek","orcid":"0000-0002-8267-1806","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:55:21.727661Z","pmid":"40313921","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}