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

摘要

Purpose: Patients with fundus albipunctatus uniformly experiencedifficulty with vision at night. Their retinas are spotted withcharacteristic light yellow flecks of unknown composition that typicallyspare the macula. A defect in the transport or utilization of visualcycle retinoids is thought to underlie this recessive disorder withvariable clinical expression. To elucidate the molecular defect weconsidered the genes for interphotoreceptor retinoid-binding protein(RBP3) and 11-cis retinol dehydrogenase (RDH5) as candidatesfor this disease.Methods: We examined two unrelated families with fundusalbipunctatus. The diagnosis was determined clinically and RBP3 andRDH5 were analyzed by molecular screening methods and direct genomicsequencing.Results: Each family had two affected members with typical fundusalbipunctatus. The affected members were siblings born to unaffectedparents who were seventh cousins in the first family and unrelated inthe second family. The probands from both families were clinicallysimilar except for the fundus dots that were more extensive in thesecond family to the point of involving the parafoveal region. In theinitial phase of genetic screening RBP3 defects were ruled-out asthe cause of the disease in both families. In contrast, RDH5mutations were found in the affected siblings in both families. Theproband in one had a homozygotic Gly238Trp missense mutation (GGG -TGG) involving exon 4 and in the other carried compound heterozygoticchanges Arg280His (CGC - CAC) and Ala294Pro (GCC - CCC) in exon5. The disease phenotype was only manifested in family members with twoabnormal RDH5 alleles consistent with autosomal recessiveinheritance in both pedigrees.Conclusions: These findings strongly implicate defects of RDH5as the cause of fundus albipunctatus and point to a heterogeneity ofRDH5 mutations in this form of congenital stationary night blindnesswith variable expressivity.