{"doi":"10.7554/elife.87147","title":"Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms","abstract":"Homeodomain transcription factors (HD TFs) are instrumental to vertebrate development. Mutations in HD TFs have been linked to human diseases, but their pathogenic mechanisms remain elusive. Here, we use Cone-Rod Homeobox ( CRX ) as a model to decipher the disease-causing mechanisms of two HD mutations, p.E80A and p.K88N, that produce severe dominant retinopathies. Through integrated analysis of molecular and functional evidence in vitro and in knock-in mouse models, we uncover two novel gain-of-function mechanisms: p.E80A increases CRX-mediated transactivation of canonical CRX target genes in developing photoreceptors; p.K88N alters CRX DNA-binding specificity resulting in binding at ectopic sites and severe perturbation of CRX target gene expression. Both mechanisms produce novel retinal morphological defects and hinder photoreceptor maturation distinct from loss-of-function models. This study reveals the distinct roles of E80 and K88 residues in CRX HD regulatory functions and emphasizes the importance of transcriptional precision in normal development.","journal":"eLife","year":2023,"id":333821,"datarank":0.7861700840958966,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"self_citation_contribution":0.47032413238937254,"citation_network_contribution":0.3158459517065241,"self_endowment_contribution":0.47032413238937254,"citer_contribution":0.3158459517065241,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":13,"citers_with_citation_signal":12,"citers_with_endowment":12,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE223659","GSE87064"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":831930,"name":"Chi Sun","orcid":"0000-0003-0656-3333","position":1,"is_corresponding":false},{"id":790978,"name":"Xiaodong Zhang","orcid":"0000-0001-9786-7038","position":2,"is_corresponding":false},{"id":268114,"name":"Philip A. Ruzycki","orcid":"0000-0003-3520-6407","position":3,"is_corresponding":false},{"id":92282,"name":"Shiming Chen","orcid":"0000-0002-9299-5767","position":4,"is_corresponding":false},{"id":92275,"name":"Yiqiao Zheng","orcid":"0000-0003-4133-0439","position":0,"is_corresponding":true}],"reference_count":129,"raw_metadata":null,"created_at":"2026-07-19T01:09:44.297718Z","pmid":"37963072","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":[]}