title: CRB1 heterozygotes with regional retinal dysfunction: implications for genetic testing of leber congenital amaurosis.
abstract: OBJECTIVE
  To test human CRB1 heterozygotes for possible clinical or functional retinal changes and to evaluate whether a patient with Leber congenital amaurosis (LCA) with CRB1 mutations not consistent with previously described CRB1 phenotypes carried a modifier allele in another LCA gene.
  
  
  METHODS
  Seven unrelated heterozygous carriers of CRB1 mutations underwent phenotyping by full eye examinations (indirect ophthalmoscopy and slit lamp biomicroscopy) and functional testing (standard full-field electroretinography [ERG] and multifocal ERG). For genotyping of the LCA patients and their parents, denaturing high-performance liquid chromatography (dHPLC) analyses were performed, followed by sequence analysis of CRB1, followed by sequence analysis of the AIPL1 and CRX genes to identify a putative modifier effect in a patient with an atypical CRB1 phenotype.
  
  
  RESULTS
  Reduced full-field ERG b-wave amplitudes were observed with scotopic -2 dB flash (140 microV; P < 0.05), normal full-field cone ERGs, and significant regional retinal dysfunction on mfERG in five of seven carriers of CRB1 mutations. A known AIPL1 mutation (p. R302L) was identified as a potential modifier allele in a patient with LCA carrying two CRB1 mutations and with a prominent maculopathy.
  
  
  CONCLUSIONS
  In human heterozygotes of CRB1 mutations (parents of offspring with LCA), distinctive regional retinal dysfunctions were found by multifocal ERG measurements that were consistent with the focal histologic abnormalities reported for the two CRB1 knockout mice models. This phenotypic finding may identify CRB1 carriers and point to the causal gene defect in affected LCA offspring, significantly facilitating the molecular diagnostic process. Evidence suggests a modifier allele in AIPL1 in a patient with LCA with prominent atrophic macular lesions and homozygous defects in CRB1.
authors.affiliation: McGill Ocular Genetics Centre, Division of Ophthalmology, Montreal, Quebec, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Yzer
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Fishman
authors.forename: Julie
authors.initials: J
authors.lastname: Racine
authors.forename: Sana
authors.initials: S
authors.lastname: Al-Zuhaibi
authors.forename: Hadi
authors.initials: H
authors.lastname: Chakor
authors.forename: Allison
authors.initials: A
authors.lastname: Dorfman
authors.forename: Janet
authors.initials: J
authors.lastname: Szlyk
authors.forename: Pierre
authors.initials: P
authors.lastname: Lachapelle
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000483:Alleles; D001766:Blindness / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D012160:Retina / Q000503:physiopathology; D012162:Retinal Degeneration / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D015534:Trans-Activators / Q000235:genetics
chemical_list: C403625:AIPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C448939:CRB1 protein, human; D002352:Carrier Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; C109288:cone rod homeobox protein