| First Author | Zheng Y | Year | 2023 |
| Journal | Elife | Volume | 12 |
| PubMed ID | 37963072 | Mgi Jnum | J:343281 |
| Mgi Id | MGI:7564617 | Doi | 10.7554/eLife.87147 |
| Citation | Zheng Y, et al. (2023) Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms. Elife 12 |
| abstractText | 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. |
