Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms.
In: BioRxiv : the preprint server for biology, 2023-06-15
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Zugriff:
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.
Competing Interests: Declaration of interests The authors declare no competing interests.
Titel: |
Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms.
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Autor/in / Beteiligte Person: | Zheng, Y ; Sun, C ; Zhang, X ; Ruzycki, PA ; Chen, S |
Zeitschrift: | BioRxiv : the preprint server for biology, 2023-06-15 |
Veröffentlichung: | 2023 |
Medientyp: | unknown |
DOI: | 10.1101/2023.02.01.526652 |
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