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CRB1 heterozygotes with regional retinal dysfunction: implications for genetic testing of leber congenital amaurosis.
- Source :
-
Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2006 Sep; Vol. 47 (9), pp. 3736-44. - Publication Year :
- 2006
-
Abstract
- Purpose: 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.<br />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.<br />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.<br />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.
- Subjects :
- Adaptor Proteins, Signal Transducing
Adult
Alleles
Blindness congenital
Blindness physiopathology
Carrier Proteins genetics
Child
Child, Preschool
Chromatography, High Pressure Liquid
Electroretinography
Female
Genetic Testing
Genotype
Heterozygote
Homeodomain Proteins genetics
Humans
Male
Middle Aged
Mutation
Pedigree
Retina physiopathology
Retinal Degeneration congenital
Retinal Degeneration physiopathology
Trans-Activators genetics
Blindness genetics
Eye Proteins genetics
Membrane Proteins genetics
Nerve Tissue Proteins genetics
Retinal Degeneration genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0146-0404
- Volume :
- 47
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Investigative ophthalmology & visual science
- Publication Type :
- Academic Journal
- Accession number :
- 16936081
- Full Text :
- https://doi.org/10.1167/iovs.05-1637