title: A mouse model for Sorsby fundus dystrophy.
abstract: OBJECTIVE
  Sorsby fundus dystrophy (SFD) is a rare, late-onset macular dystrophy caused by mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) gene. The known mutations introduce potentially unpaired cysteine residues in the C terminus of the protein and result in the formation of higher-molecular-weight protein complexes of as yet unknown composition and functional consequences in the pathologic course of SFD. To facilitate in vivo investigation of mutant TIMP3, the authors generated a knock-in mouse carrying a disease-related Ser156Cys mutation in the orthologous murine Timp3 gene.
  
  
  METHODS
  Site-directed mutagenesis and homologous recombination in embryonic stem (ES) cells was used to generate mutant ES cells carrying the Timp3(S156C) allele. Chimeric animals were obtained, of which two displayed germline transmission of the mutated allele. Molecular genetic, biochemical, electron microscopic, and electrodiagnostic techniques were used for characterization.
  
  
  RESULTS
  At 8 months of age, knock-in mice showed abnormalities in the inner aspect of Bruch's membrane and in the organization of the adjacent basal microvilli of the retinal pigment epithelium (RPE). Changes resembling those in the mutant animals were also present to some extent in normal littermates, but only at an advanced age of 30 months. Long-term electrodiagnostic recordings indicated normal retinal function throughout life. The biochemical characteristics of the mutant protein appear similar in humans and knock-in mice, suggesting common molecular pathways in the two species. The localization of the mutant protein in the eye is normal, although there is evidence of increased Timp3 levels in Bruch's membrane of mutant animals.
  
  
  CONCLUSIONS
  The knock-in mice display early features of age-related changes in Bruch's membrane and the RPE that may represent the primary clinical manifestations of SFD. In addition, our immunolabeling studies and biochemical data support a model proposing that site-specific excess rather than absence or deficiency of functional Timp3 may be the primary consequence of the known Timp3 mutations.
authors.affiliation: Institute of Human Genetics, Biocenter, University of Wuerzburg, Germany. bweb@biozentrum.uni-wuerzburg.de
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
authors.forename: Biaoyang
authors.initials: B
authors.lastname: Lin
authors.forename: Karen
authors.initials: K
authors.lastname: White
authors.forename: Konrad
authors.initials: K
authors.lastname: Kohler
authors.forename: Galina
authors.initials: G
authors.lastname: Soboleva
authors.forename: Sabine
authors.initials: S
authors.lastname: Herterich
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.forename: Gesine B
authors.initials: GB
authors.lastname: Jaissle
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
authors.forename: Charlotte
authors.initials: C
authors.lastname: Reme
authors.forename: Andreas
authors.initials: A
authors.lastname: Wenzel
authors.forename: Esther
authors.initials: E
authors.lastname: Asan
authors.forename: Heinrich
authors.initials: H
authors.lastname: Schrewe
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D004596:Electroretinography; D005260:Female; D005654:Fundus Oculi; D005822:Genetic Vectors; D008268:Macular Degeneration / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009887:Ophthalmoscopy; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000503:physiopathology; D012160:Retina / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012243:Rhodopsin / Q000502:physiology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D012243:Rhodopsin