Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes

Hum Mutat. 2005 Aug;26(2):104-12. doi: 10.1002/humu.20191.


Familial exudative vitreoretinopathy (FEVR) is a hereditary blinding disorder that features defects in retinal vascular development. The mutations in the genes encoding the Wnt receptor pair, frizzled 4 (FZD4) and low-density-lipoprotein receptor-related protein 5 (LRP5), have been shown to cause FEVR. In this study we screened 56 unrelated patients with FEVR (31 familial and 25 simplex cases) for possible mutations in LRP5 and FZD4. Six novel mutations in either LRP5 or FZD4 were identified in six familial cases. Four novel mutations in LRP5 and one known mutation in FZD4 were detected in three simplex cases, and two of these patients carried compound heterozygous mutations in LRP5. Remarkably, c.1330C>T [p.R444C] in LRP5 was found in the family in which c.1250G>A [p.R417Q] in FZD4 had previously been identified. The phenotype of these patients suggested a synergistic effect of the two mutations in the independent FEVR-causing genes. We also demonstrated that reduced bone density is a common feature in patients with FEVR who harbor LRP5 mutations. The profile of the mutations obtained in the current study further illustrates the complexity of the disease and provides a better understanding of the spectrum, frequencies, and genotype-phenotype correlation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Bone Density
  • Case-Control Studies
  • Female
  • Frizzled Receptors / genetics*
  • Genotype
  • Humans
  • LDL-Receptor Related Proteins / genetics*
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Male
  • Models, Biological
  • Mutation*
  • Osteoporosis / genetics
  • Phenotype
  • Receptors, G-Protein-Coupled / genetics*
  • Sequence Homology, Amino Acid
  • Vitreoretinopathy, Proliferative / genetics*


  • FZD4 protein, human
  • Frizzled Receptors
  • LDL-Receptor Related Proteins
  • LRP5 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Receptors, G-Protein-Coupled