Norrin (also called Norrie Disease Protein or NDP) is a secreted regulatory protein that remains tightly associated with the extracellular matrix (1). At least 70 mutations of human Norrin have been identified in Norrie disease (X-linked retinal dysplasia) or in a minority of X-linked familial exudative vitreoretinopathy (FEVR). Both are disorders of retinal vascularization that cause blindness (2, 3). Norrin consists of disulfide-linked homodimers that oligomerize further via disulfide bridges to form higher order oligomers containing up to ten 12 kDa units. The cysteine-rich C-terminal domain of Norrin shows homology to von Willebrand factor, several extracellular mucin proteins, and members of the TGF-beta family. Molecular modeling studies predict that Norrin assumes the cysteine-knot structure typical of the TGF-beta family (4). Although Norrin is not related to Wnt family proteins, it functions like a Wnt protein in that it binds with high affinity to the receptor Frizzled-4, requires LDL receptor-related protein (LRP) as a co-receptor, and induces activation of the canonical Wnt signaling pathway (5). Norrin and Frizzled-4 are widely expressed, but at relatively low levels, in tissues displaying vascular phenotypes. Genetic disruption of either Norrin or Frizzled-4 results in blindness and progressive deafness due to vascular abnormalties (5-7). Female Norrin ^-/- mice are infertile due to abnormalities in decidual vasculature (8). Mature mouse Norrin shares 97-98% aa identity with human, canine and bovine Norrin.