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FZD4 gene

frizzled class receptor 4

Normal Function

The FZD4 gene provides instructions for making a protein called frizzled-4. This protein is embedded in the outer membrane of many types of cells, where it is involved in transmitting chemical signals from outside the cell to the cell's nucleus. Specifically, frizzled-4 participates in the Wnt signaling pathway, a series of steps that affect the way cells and tissues develop. Wnt signaling is important for cell division (proliferation), attachment of cells to one another (adhesion), cell movement (migration), and many other cellular activities.

Studies suggest that, at the cell surface, the frizzled-4 protein interacts with a protein called norrin (produced from the NDP gene). The two proteins fit together like a key in a lock. Researchers suspect that when norrin attaches (binds) to frizzled-4, it initiates a multi-step process that regulates the activity of certain genes. During early development, signaling by norrin and frizzled-4 plays a critical role in the specialization of cells in the retina, which is the light-sensitive tissue that lines the back of the eye. This signaling pathway is also involved in the formation of blood vessels in the retina and in the inner ear.

Health Conditions Related to Genetic Changes

Familial exudative vitreoretinopathy

Variants (also called mutations) in the FZD4 gene have been identified in people with an eye disorder called familial exudative vitreoretinopathy. This disorder affects the retina and can cause vision loss that worsens over time. Some of these variants change single protein building blocks (amino acids) in frizzled-4, while others insert or delete genetic material in the FZD4 gene. Most FZD4 gene variants reduce the amount of frizzled-4 that is produced within cells. Other variants are thought to result in the production of an unstable protein that cannot bind to norrin.

A reduction in the amount of frizzled-4 disrupts chemical signaling in the developing eye, which interferes with the formation of blood vessels at the edges of the retina. The resulting abnormal blood supply to this tissue can lead to retinal damage and vision loss in people with familial exudative vitreoretinopathy.

More About This Health Condition

Other Names for This Gene

  • CD344
  • EVR1
  • FEVR
  • frizzled 4
  • frizzled family receptor 4
  • frizzled homolog 4 (Drosophila)
  • Fz-4
  • FZD4S
  • FzE4
  • GPCR
  • MGC34390
  • WNT receptor frizzled-4

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases


  • Kondo H, Hayashi H, Oshima K, Tahira T, Hayashi K. Frizzled 4 gene (FZD4) mutations in patients with familial exudative vitreoretinopathy with variable expressivity. Br J Ophthalmol. 2003 Oct;87(10):1291-5. doi: 10.1136/bjo.87.10.1291. Citation on PubMed or Free article on PubMed Central
  • Nallathambi J, Shukla D, Rajendran A, Namperumalsamy P, Muthulakshmi R, Sundaresan P. Identification of novel FZD4 mutations in Indian patients with familial exudative vitreoretinopathy. Mol Vis. 2006 Sep 21;12:1086-92. Citation on PubMed
  • Qin M, Hayashi H, Oshima K, Tahira T, Hayashi K, Kondo H. 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. Citation on PubMed
  • Qin M, Kondo H, Tahira T, Hayashi K. Moderate reduction of Norrin signaling activity associated with the causative missense mutations identified in patients with familial exudative vitreoretinopathy. Hum Genet. 2008 Jan;122(6):615-23. doi: 10.1007/s00439-007-0438-8. Epub 2007 Oct 23. Citation on PubMed
  • Toomes C, Bottomley HM, Jackson RM, Towns KV, Scott S, Mackey DA, Craig JE, Jiang L, Yang Z, Trembath R, Woodruff G, Gregory-Evans CY, Gregory-Evans K, Parker MJ, Black GC, Downey LM, Zhang K, Inglehearn CF. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. 2004 Apr;74(4):721-30. doi: 10.1086/383202. Epub 2004 Mar 11. Citation on PubMed or Free article on PubMed Central
  • Toomes C, Bottomley HM, Scott S, Mackey DA, Craig JE, Appukuttan B, Stout JT, Flaxel CJ, Zhang K, Black GC, Fryer A, Downey LM, Inglehearn CF. Spectrum and frequency of FZD4 mutations in familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2004 Jul;45(7):2083-90. doi: 10.1167/iovs.03-1044. Citation on PubMed
  • Warden SM, Andreoli CM, Mukai S. The Wnt signaling pathway in familial exudative vitreoretinopathy and Norrie disease. Semin Ophthalmol. 2007 Oct-Dec;22(4):211-7. doi: 10.1080/08820530701745124. Citation on PubMed
  • Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C, Kelley MW, Jiang L, Tasman W, Zhang K, Nathans J. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004 Mar 19;116(6):883-95. doi: 10.1016/s0092-8674(04)00216-8. Citation on PubMed

The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.