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MF Flynn, GA Fishman, H Yamamoto, JL Grimsby, TP Dryja; Novel CRALBP Mutations Associated With Retinitis Punctata Albescens: Further Evidence Of Genetic Heterogeneity . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1196.
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Purpose: To determine the molecular genetic defects associated with retinitis punctata albescens (RPA) in five patients from three families with this autosomal recessive disease. Methods: We evaluated three probands and two clinically affected relatives with RPA. Clinical examinations included visual fields (VFs), electroretinograms (ERGs), and fundus photographs. DNA was analyzed for mutations in the 9 exons of the RLBP1 gene (encoding CRALBP) and 5 exons of the RDH5 gene (encoding 11-cis retinol dehydrogenase). The exons were individually amplified and screened for mutations by single strand conformation analysis (SSCP) and/or direct genomic sequencing. Results: Three patients, ages 7, 9, and 21, were from one family, while the remaining two patients, ages 7 and 49, were from separate families. All complained of impaired night vision within the first or second decade of life. Visual acuity ranged from 20/20 to 20/50. Peripheral visual fields were normal. All 5 patients had multiple porcelain white dots in the mid-peripheral retina and posterior pole. Four of the 5 had pigment mottling or clumping in the mid-peripheral retina while one (age 21) did not. One patient, age 49, also showed areas of choroidal atrophy in the mid-peripheral retina. The dark-adapted isolated rod ERG responses to a low intensity blue stimulus in two patients from different families, ages 7 and 21, were either nondetectable or mildly subnormal, respectively, even after 17 hours of overnight patching. The latter patient did show a 30% increase in the isolated rod b-wave amplitude after 17 hours of dark adaptation as compared to the amplitude after 40-minutes of dark adaptation. The dark-adapted maximal ERG b-wave amplitude after 40 minutes of dark adaptation was within 60 µV of the light-adapted high-intensity b-wave amplitude in 4 of the 5 patients, reflecting a marked impairment of rod function. The molecular genetic analysis results were negative for a RDH5 mutation in the three probands. Novel compound heterozygous mutations in the RLBP1 gene were found in one of three probands (age 7, isolated case). One mutation was a frameshift Gly31 (2-bp deletion) (GGA≷G--) change and the other a missense Arg151Trp (CGG≷TGG) change. Conclusion: The identification of novel RLBP1 gene mutations in only one of our three probands, all with an RPA phenotype, is evidence of genetic (nonallelic) heterogeneity in this disease.
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