Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization

Nat Cell Biol. 2004 Jan;6(1):52-8. doi: 10.1038/ncb1081. Epub 2003 Dec 14.


nt signalling pathways regulate cell proliferation, cell fate and morphogenetic movements. Here, we demonstrate that the Frizzled (Fz) family of Wnt receptors, similarly to G-protein-coupled receptors (GPCRs), form specific homo- and hetero-oligomers. Two lines of evidence suggest that oligomerization occurs in the endoplasmic reticulum: first, a mutant allele of Fz4, encoding a truncated protein that is retained in the endoplasmic reticulum, is linked to the autosomal-dominant retinal degenerative disease, familial exudative vitreoretinopathy (FEVR). We show that this mutant form of Fz4 oligomerizes with wild-type Fz4, retains it in the endoplasmic reticulum and inhibits its signalling. Second, a derivative of Fz1 targeted to the endoplasmic reticulum traps wild-type Fz1 in the endoplasmic reticulum and blocks its signalling. These data support the hypothesis that oligomerization of mutant and wild-type Fz proteins occurs in the endoplasmic reticulum and may explain the genetic dominance of this FEVR allele.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • COS Cells
  • Endoplasmic Reticulum / metabolism*
  • Frizzled Receptors
  • Genes, Dominant / genetics
  • Humans
  • Mutation / genetics
  • Peptide Fragments / metabolism
  • Proteins / genetics*
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Receptors, Neurotransmitter / metabolism
  • Signal Transduction / genetics
  • Vitreoretinopathy, Proliferative / genetics*
  • Wnt Proteins
  • Zebrafish Proteins*


  • FZD1 protein, human
  • FZD4 protein, human
  • Frizzled Receptors
  • Peptide Fragments
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Receptors, Neurotransmitter
  • Wnt Proteins
  • Zebrafish Proteins