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S.S. Al–Zuhaibi, I. Lopez, G.A. Fishman, H. Chakor, J. Racine, P. Lachapelle, A. den Hollander, F.P. M. Cremers, R. Allikmets, R.K. Koenekoop; Heterozygous Carriers (Parents of Offspring With Leber Congenital Amaurosis) With CRB1 Mutations Have a Focal Retinal Dysfunction . Invest. Ophthalmol. Vis. Sci. 2005;46(13):538.
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Purpose: Recessive mutations in the Crumbs homolog–1 gene, CRB1, cause Leber congenital amaurosis (LCA). The CRB1 protein is involved in photoreceptor structure and development, while the CRB1 knockout mouse shows a focal retinal dystrophy. We have thusfar found gene–specific phenotypes in obligate heterozygotes with GUCY2D, RPE65, AIPL1, and RPGRIP1 mutations from LCA families. We tested the hypothesis that CRB1 heterozygotes have a phenotype specific for the CRB1 defect. We specifically looked for mosaic retinal changes by multifocal ERG, which may correlate with the mouse CRB1 phenotype. Methods: We are screening all LCA genes in ∼500 patients by a combination of technologies including the new LCA microarray (Asper), dHPLC wave analysis (Transgenomics), and automated sequencing (ABI, Perkin Elmer). The mutations were then traced to the parents and they underwent full eye examinations (indirect ophthalmoscopy and slit lamp biomicroscopy) and functional testing which consisted of electroretinography (ERG), multifocal ERG (mfERG), and photopic hill analysis. Results: All study parents have children with LCA and proven mutations in CRB1. We are evaluating the phenotype of 10 heterozygous carriers with CRB1 mutations (p.R905Q, several p.C948Y and p.V1336I). One parent had inferior white retinal dots, while all others had retinal arteriolar thinning. We found abnormal b–wave amplitudes with scotopic –2dB flash (140 µV, p<0.05), normal full field cone ERGs, abnormal photopic hills, and significant inferior focal areas of retinal dysfunction on mfERG in some of the carriers. Conclusions: The mosaic pattern of inferior retinal dysfunction found in some human heterozygotes of CRB1 mutations correlates with the CRB1 knockout mouse phenotype. Functional testing of CRB1 heterozygotes provides important physiological information of the retinal dystrophy in the offspring with LCA. Also, these relatively simple clinical tests on the parents suggests the molecular defect in the children with LCA and fascilitates subsequent molecular diagnostic testing.
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