title: Pigmented paravenous chorioretinal atrophy is associated with a mutation within the crumbs homolog 1 (CRB1) gene.
abstract: OBJECTIVE
  Pigmented paravenous chorioretinal atrophy (PPCRA) is an unusual retinal degeneration characterized by accumulation of pigmentation along retinal veins. The purpose of this study was to describe the phenotype of a family with PPCRA, determine the mode of inheritance, and identify the causal mutation.
  
  
  METHODS
  Ophthalmic examination was performed on seven family members and serially detailed in the proband over a 3-year period. Blood samples were collected and DNA extracted. All 12 coding exons and the 5' promoter region of the crumbs homologue 1 (CRB1) gene were PCR amplified and DNA sequenced. In silico homology modeling was performed on the mutated protein domain.
  
  
  RESULTS
  Subtle symmetrical chorioretinal atrophy in the inferior quadrant was the earliest clinical sign detectable within this family. Paravenous pigmentation occurred initially in the far periphery, progressing centrally, with atrophy later becoming more widespread, involving the nasal, then the temporal, and finally the upper quadrant. A novel, dominant Val162Met mutation within the fourth EGF-like domain of CRB1 cosegregates with the PPCRA phenotype. It is thought to affect domain structure, because codon 162 is involved in hydrogen bonding between the antiparallel beta-strands of the major beta-sheet, causing sufficient perturbation of the backbone that the domain-stabilizing hydrogen bond does not form or is weakened.
  
  
  CONCLUSIONS
  PPCRA was dominantly inherited in this family, but exhibited variable expressivity. Males are more likely to exhibit a severe phenotype, whereas females may remain virtually asymptomatic even in later years. The PPCRA phenotype is associated with a Val162Met mutation in CRB1 which is likely to affect the structure of the CRB1 protein.
authors.affiliation: Ophthalmic Research Centre, Institute of Clinical Science, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: McKay
authors.forename: Stephen
authors.initials: S
authors.lastname: Clarke
authors.forename: Jason A
authors.initials: JA
authors.lastname: Davis
authors.forename: David A C
authors.initials: DA
authors.lastname: Simpson
authors.forename: Giuliana
authors.initials: G
authors.lastname: Silvestri
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001284:Atrophy; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D012169:Retinal Vein / Q000473:pathology*; D041623:Tomography, Optical Coherence
chemical_list: C448939:CRB1 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins