A model for familial exudative vitreoretinopathy caused by LPR5 mutations.

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Amino-Acid-Substitution, Animals, Capillaries, Disease-Models-Animal, Ethylnitrosourea, Exons, Frameshift-Mutation, Homozygote, LDL-Receptor-Related-Proteins, Male, Mice-Knockout, Molecular-Sequence-Data, Mutagenesis, Mutagenesis-Insertional, Protein-Structure-Tertiary, Retinal-Diseases, Retinal-Vessels

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Hum Mol Genet 2008 Jun; 17(11):1605-12.


We have identified a mouse recessive mutation that leads to attenuated and hyperpermeable retinal vessels, recapitulating some pathological features of familial exudative vitreoretinopathy (FEVR) in human patients. DNA sequencing reveals a single nucleotide insertion in the gene encoding the low-density lipoprotein receptor-related protein 5 (LRP5), causing a frame shift and resulting in the replacement of the C-terminal 39 amino acid residues by 20 new amino acids. This change eliminates the last three PPP(S/T)P repeats in the LRP5 cytoplasmic domain that are important for mediating Wnt/beta-catenin signaling. Thus, mutant LRP5 protein is probably unable to mediate its downstream signaling. Immunostaining and three-dimensional reconstructions of retinal vasculature confirm attenuated retinal vessels. Ultrastructural data further reveal that some capillaries lack lumen structure in the mutant retina. We have also verified that LRP5 null mice develop similar alterations in the retinal vasculature. This study provides direct evidence that LRP5 is essential for the development of retinal vasculature, and suggests a novel role played by LRP5 in capillary maturation. LRP5 mutant mice can be a useful model to explore the clinical manifestations of FEVR.