title: Identification and functional characterization of a novel rhodopsin mutation associated with autosomal dominant CSNB.
abstract: OBJECTIVE
  Mutations in RHO, PDE6B, and GNAT1 can lead to autosomal dominant congenital stationary night blindness (adCSNB). The study was conducted to identify the genetic defect in a large Swiss family affected with adCSNB and to investigate the pathogenic mechanism of the mutation.
  
  
  METHODS
  Two affected cousins of a large Swiss family were examined clinically by standard methods: funduscopy, EOG, ERG, and dark adaptometry. Twelve family members were screened for mutations in RHO. The ability of mutant rhodopsin to activate transducin constitutively was monitored by measuring the catalytic exchange of bound GDP for radiolabeled [(35)S]GTPgammaS in transducin.
  
  
  RESULTS
  A novel mutation was identified in RHO (c.884C>T, p.Ala295Val) in patients with adCSNB. They had full vision under photopic conditions, showed no fundus abnormalities, revealed EOG results in the normal range, but presented night blindness with an altered scotopic ERG. In the presence of 11-cis retinal, the mutant rhodopsin is inactive, similar to wild-type, responding only when exposed to light. However, in the absence of 11-cis-retinal, unlike wild-type opsin, the mutant opsin constitutively activates transducin.
  
  
  CONCLUSIONS
  The study adds a fourth rhodopsin mutation associated with CSNB. Although the phenotype of autosomal dominant CSNB may vary slightly in patients showing mutations in RHO, PDE6B, or GNAT1, the disease course seems to be stationary with only scotopic vision being affected. The data indicate that the mutant opsin activates transducin constitutively, which is a consistent and common feature of all four CSNB-associated rhodopsin mutations reported to date.
authors.affiliation: Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Zurich, Switzerland. christina.zeitz@inserm.fr
authors.forename: Christina
authors.initials: C
authors.lastname: Zeitz
authors.forename: Alecia K
authors.initials: AK
authors.lastname: Gross
authors.forename: Dorothee
authors.initials: D
authors.lastname: Leifert
authors.forename: Barbara
authors.initials: B
authors.lastname: Kloeckener-Gruissem
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: McAlear
authors.forename: Johannes
authors.initials: J
authors.lastname: Lemke
authors.forename: John
authors.initials: J
authors.lastname: Neidhardt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
mesh_terms: D000064:Acclimatization; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics*; D004252:DNA Mutational Analysis; D003624:Darkness; D004585:Electrooculography; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D009755:Night Blindness / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D012234:Rho Factor / Q000235:genetics; D012243:Rhodopsin / Q000235:genetics*; D015293:Transducin; D014794:Visual Fields
chemical_list: D005136:Eye Proteins; C034809:GNAT1 protein, human; D012234:Rho Factor; D012243:Rhodopsin; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517431:PDE6B protein, human; D020962:Heterotrimeric GTP-Binding Proteins; D015293:Transducin