11-cis Retinol dehydrogenase mutations as a major cause of the congenital night-blindness disorder known as fundus albipunctatus

PURPOSE: Patients with fundus albipunctatus uniformly experience difficulty with vision at night. Their retinas are spotted with characteristic light yellow flecks of unknown composition that typically spare the macula. A def ect in the transport or utilization of visual cycle retinoids is thought to underlie this recessive disorder with variable clinical expression. To elu cidate the molecular defect we considered the genes for interphotoreceptor retinoid-binding protein (RBP3) and 11-cis retinol dehydrogenase (RDH5) as candidates for this disease. METHODS: We examined two unrelated families with fundus albipunctatus. The diagnosis was determined clinically and RBP3 and RDH5 were analyzed by mole cular screening methods and direct genomic sequencing. RESULTS: Each family had two affected members with typical fundus albipunct atus. The affected members were siblings born to unaffected parents who wer e seventh cousins in the first family and unrelated in the second family. T he probands from both families were clinically similar except for the fundu s dots that were more extensive in the second family to the point of involv ing the parafoveal region. In the initial phase of genetic screening RBP3 d efects were ruled-out as the cause of the disease in both families. In cont rast, RDH5 mutations were found in the affected siblings in both families. The proband in one had a homozygotic Gly238Trp missense mutation (GGG --> T GG) involving exon 4 and in the other carried compound heterozygotic change s Arg280His (CGC --> CAC) and Ala294Pro (GCC --> CCC) in exon 5. The diseas e phenotype was only manifested in family members with two abnormal RDH5 al leles consistent with autosomal recessive inheritance in both pedigrees. CONCLUSIONS: These findings strongly implicate defects of RDH5 as the cause of fundus albipunctatus and point to a heterogeneity of RDH5 mutations in this form of congenital stationary night blindness with variable expressivi ty.