Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms

• Published in: eLife Vol. 12
• Main Authors: Zheng, Yiqiao, Sun, Chi, Zhang, Xiaodong, Ruzycki, Philip A, Chen, Shiming
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 14.11.2023
• Subjects: Animal models; Animals; CRX disease mutations; CRX protein; Disease; DNA-binding specificity; Energy; Experiments; Gene expression; Homeobox; homeodomain; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; inherited retinal diseases; Mice; Missense mutation; Mutation; Mutation, Missense; photoreceptor development; Photoreceptors; Retina; Retina - metabolism; Retinal Diseases - pathology; Trans-Activators - genetics; Trans-Activators - metabolism; transcription factor; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; mouse; photoreceptor development; transcription factor; inherited retinal diseases; DNA-binding specificity; genetics; homeodomain; neuroscience; genomics; CRX disease mutations
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.87147

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 ( ) 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.