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S. Dharmaraj, I. Lopez, G. Fishman, J. Racine, A. Dorfman, P. Lachapelle, I. Maumenee, F. Cremers, R. Allikmets, R. Koenekoop; Recessive RPGRIP1 mutations can cause rod and cone dysfunction in the heterozygous parents. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4728.
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Purpose: The RPGRIP1 (the retinitis pigmentosa GTPase interacting protein) gene, encodes a protein that localizes to the connecting cilium of both rod and cone photoreceptors. Recessive mutations in this gene cause Leber congenital amaurosis (LCA), an autosomal recessive, severe retinal dystrophy. We tested the hypothesis that heterozygous parents of LCA patients, obligate carriers of mutant RPGRIP1 alleles, have an identifiable ERG phenotype, specific for the RPGRIP1 defect. Methods: Mutation detection was performed by PCR, dHPLC wave analysis (Transgenomics), automated sequencing (ABI, Perkin Elmer), and restriction enzyme confirmation. Full eye examinations and electroretinographic (ERG) studies were performed on four LCA families with mutations. Seven (out of 8) heterozygotes with RPGRIP1 mutations were available for ERG evaluations. We tested whether the RPGRIP1 mutation originated on the maternal (m), or paternal (p) allele. Results: In family I, we found P882S (m)/D1114G (p) mutations. In family II, we discovered R768X (p)/IVS 23–1G>A (m) mutations. In families III and IV, we found the heterozygous Q483X (p) and T806I (p), mutations, respectively. In families I and III both parents had abnormally decreased rod and cone b–wave amplitudes (up to 50%), while in family II, the father had abnormally decreased rod and cone b–wave amplitudes (up to 50%), while the mother (with the splice site mutation) had an essentially normal ERG. In family IV, the mother had a normal ERG. Conclusions: Classic genetics suggests that heterozygous parents of children with autosomal recessive diseases usually do not present with a phenotype as the result of a wildtype allele. We show that some (5/7) recessive RPGRIP1 mutations cause both rod and cone photoreceptor dysfunction in the heterozygous state, while others (2/7) do not. The ERG may provide a functional assay of the deleterious effect of recessive RPGRIP1 mutations in heterozygous carriers whom do not exhibit overt retinal disease. Also, an ERG on parents with children who are blind because of LCA may help to better focus subsequent molecular diagnostics.
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