Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms
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 mutation...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/87147 |
| _version_ | 1797627872641286144 |
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| author | Yiqiao Zheng Chi Sun Xiaodong Zhang Philip A Ruzycki Shiming Chen |
| author_facet | Yiqiao Zheng Chi Sun Xiaodong Zhang Philip A Ruzycki Shiming Chen |
| author_sort | Yiqiao Zheng |
| collection | DOAJ |
| 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 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. |
| first_indexed | 2024-03-11T10:31:43Z |
| format | Article |
| id | doaj.art-6fb6d80a3f3c4ac6a89bbf37b214b857 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-11T10:31:43Z |
| publishDate | 2023-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-6fb6d80a3f3c4ac6a89bbf37b214b8572023-11-14T17:33:29ZengeLife Sciences Publications LtdeLife2050-084X2023-11-011210.7554/eLife.87147Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanismsYiqiao Zheng0https://orcid.org/0000-0003-4133-0439Chi Sun1Xiaodong Zhang2Philip A Ruzycki3Shiming Chen4https://orcid.org/0000-0002-9299-5767Molecular Genetic and Genomics Graduate Program, Division of Biological and Biomedical Sciences, Washington University in St Louis, Saint Louis, United States; Department of Ophthalmology and Visual Sciences, Washington University in St Louis, Saint Louis, United StatesMolecular Genetic and Genomics Graduate Program, Division of Biological and Biomedical Sciences, Washington University in St Louis, Saint Louis, United States; Department of Ophthalmology and Visual Sciences, Washington University in St Louis, Saint Louis, United StatesDepartment of Ophthalmology and Visual Sciences, Washington University in St Louis, Saint Louis, United StatesDepartment of Ophthalmology and Visual Sciences, Washington University in St Louis, Saint Louis, United States; Department of Genetics, Washington University in St Louis, Saint Louis, United StatesMolecular Genetic and Genomics Graduate Program, Division of Biological and Biomedical Sciences, Washington University in St Louis, Saint Louis, United States; Department of Ophthalmology and Visual Sciences, Washington University in St Louis, Saint Louis, United States; Department of Developmental Biology, Washington University in St Louis, Saint Louis, United StatesHomeodomain 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.https://elifesciences.org/articles/87147homeodomaintranscription factorDNA-binding specificityCRX disease mutationsinherited retinal diseasesphotoreceptor development |
| spellingShingle | Yiqiao Zheng Chi Sun Xiaodong Zhang Philip A Ruzycki Shiming Chen Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms eLife homeodomain transcription factor DNA-binding specificity CRX disease mutations inherited retinal diseases photoreceptor development |
| title | Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms |
| title_full | Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms |
| title_fullStr | Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms |
| title_full_unstemmed | Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms |
| title_short | Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms |
| title_sort | missense mutations in crx homeodomain cause dominant retinopathies through two distinct mechanisms |
| topic | homeodomain transcription factor DNA-binding specificity CRX disease mutations inherited retinal diseases photoreceptor development |
| url | https://elifesciences.org/articles/87147 |
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