title: Genotype-phenotype correlation of mouse pde6b mutations.
abstract: OBJECTIVE
  To identify the underlying molecular defects causing retinal degeneration in seven N-ethyl-N-nitrosourea (ENU) induced mutant alleles of the Pde6b gene and to analyze the timescale of retinal degeneration in these new models of retinitis pigmentosa.
  
  
  METHODS
  Conformation sensitive capillary electrophoresis and DNA sequencing were used to identify the mutations in the Pde6b gene. Visual acuity testing was performed with a visual-tracking drum at ages ranging from postnatal day 25 to week 10. Retinal examination was performed with an indirect ophthalmoscope. Animals were killed and eyes were prepared for histologic analysis.
  
  
  RESULTS
  Point mutations in the seven new alleles of Pde6b were identified: Three generated premature stop codons, two were missense mutations, and two were splice mutations. The three stop codon mutants and one of the splice mutants had phenotypes indistinguishable from the Pde6b(rd1) mouse in rapidity of onset of retinal degeneration, suggesting that they are null alleles. However, the remaining alleles showed slower onset of retinal degeneration, as determined by visual acuity testing, fundus examination, and histology, indicating that they are hypomorphic alleles.
  
  
  CONCLUSIONS
  These data demonstrate a correlation between genotype and phenotype. Four of the mutants with severe genetic lesions have rapid onset of retinal degeneration, as determined by fundus examination. These mice were indistinguishable from Pde6b(rd1) mice, which are effectively blind by 3 weeks of age. In contrast, the milder genetic lesions show a slower progression of the disease and provide the community with models that more closely mimic human retinitis pigmentosa.
authors.affiliation: MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK. alan.hart@hgu.mrc.ac.uk
authors.forename: Alan W
authors.initials: AW
authors.lastname: Hart
authors.forename: Lisa
authors.initials: L
authors.lastname: McKie
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Morgan
authors.forename: Philippe
authors.initials: P
authors.lastname: Gautier
authors.forename: Katrine
authors.initials: K
authors.lastname: West
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jackson
authors.forename: Sally H
authors.initials: SH
authors.lastname: Cross
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000483:Alleles; D000818:Animals; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D019075:Electrophoresis, Capillary; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009154:Mutation; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D012162:Retinal Degeneration / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014792:Visual Acuity
chemical_list: D000477:Alkylating Agents; D010727:Phosphoric Diester Hydrolases; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517431:PDE6B protein, human; C517438:Pde6b protein, mouse; D005038:Ethylnitrosourea