{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Zheng Y"],"funding":["NEI NIH HHS"],"pubmed_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 <i>Cone-Rod Homeobox (CRX)</i> as a model to decipher the disease-causing mechanisms of two HD mutations, <i>p.E80A</i> and <i>p.K88N</i>, that produce severe dominant retinopathies. Through integrated analysis of molecular and functional evidence <i>in vitro</i> and in knock-in mouse models, we uncover two novel gain-of-function mechanisms: <i>p.E80A</i> increases CRX-mediated transactivation of canonical CRX target genes in developing photoreceptors; <i>p.K88N</i> alters CRX DNA-binding specificity resulting in binding at ectopic sites and severe perturbation of CRX target gene expression"],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2023.02.01.526652"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9915647"],"repository":["biostudies-literature"],"pubmed_title":["Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms."],"pmcid":["PMC9915647"],"funding_grant_id":["R01 EY012543","R01 EY025272","R01 EY032136","P30 EY002687"],"pubmed_authors":["Ruzycki PA","Zheng Y","Sun C","Zhang X","Chen S"],"additional_accession":[]},"is_claimable":false,"name":"Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms.","description":"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 <i>Cone-Rod Homeobox (CRX)</i> as a model to decipher the disease-causing mechanisms of two HD mutations, <i>p.E80A</i> and <i>p.K88N</i>, that produce severe dominant retinopathies. Through integrated analysis of molecular and functional evidence <i>in vitro</i> and in knock-in mouse models, we uncover two novel gain-of-function mechanisms: <i>p.E80A</i> increases CRX-mediated transactivation of canonical CRX target genes in developing photoreceptors; <i>p.K88N</i> alters CRX DNA-binding specificity resulting in binding at ectopic sites and severe perturbation of CRX target gene expression","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jun","modification":"2026-06-27T03:20:20.105Z","creation":"2025-02-19T02:23:53.845Z"},"accession":"S-EPMC9915647","cross_references":{"pubmed":["36778408"],"doi":["10.1101/2023.02.01.526652"]}}