title: A mutagenesis-derivedLrp5mouse mutant with abnormal retinal vasculature and low bone mineral density.
abstract: Familial exudative vitreoretinopathy (FEVR) is caused by mutations in the genes encoding low-density lipoprotein receptor-related protein (LRP5) or its interacting partners, namely frizzled class receptor 4 (FZD4) and norrin cystine knot growth factor (NDP). Mouse models forLrp5,Fzd4, andNdphave proven to be important for understanding the retinal pathophysiology underlying FEVR and systemic abnormalities related to defective Wnt signaling. Here, we report a new mouse mutant,tvrm111B, which was identified by electroretinogram (ERG) screening of mice generated in the Jackson Laboratory Translational Vision Research Models (TVRM) mutagenesis program.
  
  
  
  ERGs were used to examine outer retinal physiology. The retinal vasculature was examined byin vivoretinal imaging, as well as by histology and immunohistochemistry. Thetvrm111Blocus was identified by genetic mapping of mice generated in a cross to DBA/2J, and subsequent sequencing analysis. Gene expression was examined by real-time PCR of retinal RNA. Bone mineral density (BMD) was examined by peripheral dual-energy X-ray absorptiometry.
  
  
  
  Thetvrm111Ballele is inherited as an autosomal recessive trait. Genetic mapping of the decreased ERG b-wave phenotype oftvrm111Bmice localized the mutation to a region on chromosome 19 that includedLrp5. Sequencing ofLrp5identified the insertion of a cytosine (c.4724_4725insC), which is predicted to cause a frameshift that disrupts the last three of five conserved PPPSPxS motifs in the cytoplasmic domain of LRP5, culminating in a premature termination. In addition to a reduced ERG b-wave,Lrp5tvrm111Bhomozygotes have low BMD and abnormal features of the retinal vasculature that have been reported previously inLrp5mutant mice, including persistent hyaloid vessels, leakage on fluorescein angiography, and an absence of the deep retinal capillary bed.
  
  
  
  The phenotype of theLrp5tvrm111Bmutant includes abnormalities of the retinal vasculature and of BMD. This model may be a useful resource to further our understanding of the biological role of LRP5 and to evaluate experimental therapies for FEVR or other conditions associated with LRP5 dysfunction.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Charette
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Cole Eye Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Earp
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Bell
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME; Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, NY.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Ackert-Bicknell
authors.affiliation: Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, NY.
authors.forename: Dana A
authors.initials: DA
authors.lastname: Godfrey
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Cole Eye Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Sujata
authors.initials: S
authors.lastname: Rao
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Cole Eye Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Bela
authors.initials: B
authors.lastname: Anand-Apte
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME.
authors.forename: Patsy M
authors.initials: PM
authors.lastname: Nishina
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Cole Eye Institute, Cleveland Clinic, Cleveland, OH; Louis Stokes Cleveland VA Medical Center, Cleveland, OH.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Peachey
mesh_terms: D000818:Animals; D015519:Bone Density; D004596:Electroretinography; D005786:Gene Expression Regulation; D006720:Homozygote; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics*; D008297:Male; D008810:Mice, Inbred C57BL; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009929:Organ Size / Q000235:genetics; D010641:Phenotype; D012171:Retinal Vessels / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D060492:Low Density Lipoprotein Receptor-Related Protein-5