title: Mechanisms of blindness: animal models provide insight into distinct CRX-associated retinopathies.
abstract: BACKGROUND
  The homeodomain transcription factor CRX is a crucial regulator of mammalian photoreceptor gene expression. Mutations in the human CRX gene are associated with dominant inherited retinopathies Retinitis Pigmentosa (RP), Cone-Rod Dystrophy (CoRD), and Leber Congenital Amaurosis (LCA), of varying severity. In vitro and in vivo assessment of mutant CRX proteins have revealed pathogenic mechanisms for several mutations, but no comprehensive mutation-disease correlation has yet been reported.
  
  
  RESULTS
  Here we describe four different classes of disease-causing CRX mutations, characterized by mutation type, pathogenetic mechanism, and the molecular activity of the mutant protein: (1) hypomorphic missense mutations with reduced DNA binding, (2) antimorphic missense mutations with variable DNA binding, (3) antimorphic frameshift/nonsense mutations with intact DNA binding, and (4) antimorphic frameshift mutations with reduced DNA binding. Mammalian models representing three of these classes have been characterized.
  
  
  CONCLUSIONS
  Models carrying Class I mutations display a mild dominant retinal phenotype and recessive LCA, while models carrying Class III and IV mutations display characteristically distinct dominant LCA phenotypes. These animal models also reveal unexpected pathogenic mechanisms underlying CRX-associated retinopathies. The complexity of genotype-phenotype correlation for CRX-associated diseases highlights the value of developing comprehensive "true-to-disease" animal models for understanding pathologic mechanisms and testing novel therapeutic approaches.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Tran
authors.forename: Shiming
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D001766:Blindness / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D010870:Pineal Gland / Q000378:metabolism / Q000473:pathology; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000235:genetics* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C109288:cone rod homeobox protein
keywords: antimorph; disease models; dominant-negative; gene expression; human genetics; hypomorph; neural development; neuronal degeneration; photoreceptors; retina; transcription factors