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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus synthetic construct

PROVIDER: GSE223659 | GEO | 2023/11/08

REPOSITORIES: GEO

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Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [Spec-seq]

Project 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 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 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 hinders 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.

2023-11-08 | GSE223658 | GEO

Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [ChIP-seq]

2023-11-08 | GSE223657 | GEO