title: Human CRB1-associated retinal degeneration: comparison with the rd8 Crb1-mutant mouse model.
abstract: OBJECTIVE
  To investigate the human disease due to CRB1 mutations and compare results with the Crb1-mutant rd8 mouse.
  
  
  METHODS
  Twenty-two patients with CRB1 mutations were studied. Function was assessed with perimetry and electroretinography (ERG) and retinal structure with optical coherence tomography (OCT). Cortical structure and function were quantified with magnetic resonance imaging (MRI). Rd8 mice underwent ERG, OCT, and retinal histopathology.
  
  
  RESULTS
  Visual acuities ranged from 20/25 to light perception. Rod ERGs were not detectable; small cone signals were recordable. By perimetry, small central visual islands were separated by midperipheral scotomas from far temporal peripheral islands. The central islands were cone mediated, whereas the peripheral islands retained some rod function. With OCT, there were small foveal islands of thinned outer nuclear layer (ONL) surrounded by thick delaminated retina with intraretinal hyperreflective lesions. MRI showed structurally normal optic nerves and only subtle changes to occipital lobe white and gray matter. Functional MRI indicated that whole-brain responses from patients were of reduced amplitude and spatial extent compared with those of normal controls. Rd8 mice had essentially normal ERGs; OCT and histopathology showed patchy retinal disorganization with pseudorosettes more pronounced in ventral than in dorsal retina. Photoreceptor degeneration was associated with dysplastic regions.
  
  
  CONCLUSIONS
  CRB1 mutations lead to early-onset severe loss of vision with thickened, disorganized, nonseeing retina. Impaired peripheral vision can persist in late disease stages. Rd8 mice also have a disorganized retina, but there is sufficient photoreceptor integrity to produce largely normal retinal function. Differences between human and mouse diseases will complicate proof-of-concept studies intended to advance treatment initiatives.
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Aguirre
authors.forename: Wei Chieh
authors.initials: WC
authors.lastname: Huang
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Mullins
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.forename: Melani B
authors.initials: MB
authors.lastname: Olivares
authors.forename: Frank F
authors.initials: FF
authors.lastname: Tsai
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: Luk H
authors.initials: LH
authors.lastname: Vandenberghe
authors.forename: Maria P
authors.initials: MP
authors.lastname: Limberis
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D004596:Electroretinography; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D011379:Prognosis; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D055815:Young Adult
chemical_list: C448939:CRB1 protein, human; C453730:Crb1 protein, mouse; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D004247:DNA