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Evidence of Interfamilial Genetic Heterogeneity and Fundus Changes in Heterozygotes

Gerald A. Fishman, MD; Mary Flynn Roberts, OD; Deborah J. Derlacki, BA; Jonna L. Grimsby, BA; Hiroyuki Yamamoto, MD, PhD; Dror Sharon, PhD; Koji M. Nishiguchi, MD; Thaddeus P. Dryja, MD

Arch Ophthalmol. 2004;122:70-75.

Objective  To evaluate the molecular genetic defects associated with retinitis punctata albescens (RPA) in 5 patients from 3 families with this disease.

Methods  We examined 3 probands and 2 clinically affected relatives with RPA. Clinical examinations included best-corrected visual acuity, visual field testing, electroretinography, dilated fundus examination, and fundus photography. Leukocyte DNA was analyzed for mutations in the exons of the genes encoding cellular retinaldehyde–binding protein 1 (RLBP1), 11-cis-retinol dehydrogenase (RDH5), interphotoreceptor retinoid–binding protein (RBP3), and photoreceptor all-trans-retinol dehydrogenase (RDH8). Not all patients were evaluated for mutations in each gene. The exons were individually amplified and screened for mutations by single-stranded conformational polymorphism analysis or direct genomic sequencing.

Results  The 3 probands had similar clinical findings, including a history of poor night vision, the presence of punctate white deposits in the retina, and substantially reduced or absent rod responses on electroretinogram testing. One of the probands (patient 2:III:2) had 2 novel mutations in the RLBP1 gene (Arg151Trp and Gly31[2–base pair deletion], [GGAG–]). Segregation analysis showed that the 2 mutations were allelic and that the patient was a compound heterozygote. Both parents of the proband manifested round white deposits in the retina. The other 2 probands had no detected pathogenic mutations in RLBP1 or in the other 3 genes evaluated.

Conclusions  The identification of novel RLBP1 mutations in 1 of our 3 probands, all with RPA, is further evidence of genetic (nonallelic) heterogeneity in this disease. The presence of round white deposits in the retina may be observed in those heterozygous for RLBP1.

Clinical Relevance  Patients with a clinical presentation of RPA can have genetically different mutations. Drusen-like lesions may be observed in heterozygotes in families with this disease and a mutation in RLBP1.

From the Department of Ophthalmology and Visual Sciences, UIC Eye Center, University of Illinois at Chicago (Dr Fishman and Ms Derlacki), and Illinois Eye Institute, Illinois College of Optometry (Dr Roberts), Chicago; and Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston (Ms Grimsby and Drs Yamamoto, Sharon, Nishiguchi, and Dryja). The authors have no relevant financial interest in this article.

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