title: 11-cis retinol dehydrogenase mutations as a major cause of the congenital night-blindness disorder known as fundus albipunctatus.
abstract: OBJECTIVE
  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 defect in the transport or utilization of visual cycle retinoids is thought to underlie this recessive disorder with variable clinical expression. To elucidate 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 molecular screening methods and direct genomic sequencing.
  
  
  RESULTS
  Each family had two affected members with typical fundus albipunctatus. The affected members were siblings born to unaffected parents who were seventh cousins in the first family and unrelated in the second family. The probands from both families were clinically similar except for the fundus dots that were more extensive in the second family to the point of involving the parafoveal region. In the initial phase of genetic screening RBP3 defects were ruled-out as the cause of the disease in both families. In contrast, RDH5 mutations were found in the affected siblings in both families. The proband in one had a homozygotic Gly238Trp missense mutation (GGG -> TGG) involving exon 4 and in the other carried compound heterozygotic changes Arg280His (CGC -> CAC) and Ala294Pro (GCC -> CCC) in exon 5. The disease phenotype was only manifested in family members with two abnormal RDH5 alleles 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 expressivity.
authors.affiliation: Departments of Ophthalmology and Pathology (Neuropathology), Graduate Program in Neuroscience, University of Virginia Health Sciences Center Charlottesville, VA 22908, USA. fg2z@Virginia.edu
authors.forename: F
authors.initials: F
authors.lastname: Gonzalez-Fernandez
authors.forename: D
authors.initials: D
authors.lastname: Kurz
authors.forename: Y
authors.initials: Y
authors.lastname: Bao
authors.forename: S
authors.initials: S
authors.lastname: Newman
authors.forename: B P
authors.initials: BP
authors.lastname: Conway
authors.forename: J E
authors.initials: JE
authors.lastname: Young
authors.forename: D P
authors.initials: DP
authors.lastname: Han
authors.forename: S C
authors.initials: SC
authors.lastname: Khani
mesh_terms: D000328:Adult; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D001483:Base Sequence; D004247:DNA / Q000737:chemistry; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005136:Eye Proteins; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D009755:Night Blindness / Q000151:congenital / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D012164:Retinal Diseases / Q000151:congenital / Q000235:genetics*; D012177:Retinol-Binding Proteins / Q000235:genetics*; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D000429:Alcohol Oxidoreductases; D004247:DNA; D005136:Eye Proteins; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C022520:retinol dehydrogenase