Wnts are not the only ligands of the FZD receptors. The cysteine-knot protein Norrin, encoded by the NDP gene, can also bind and activate Wnt receptors. In humans, NDP mutations cause Norrie disease, an X-linked disorder characterized by hypovascularization of the retina and a severe loss of visual function (Xu et al, 2004). Norrin binds with high affinity and specificity to FZD-4 (Shen et al, 2015), while coexpression of Norrin, FZD-4, and LRP5 potently activates Wnt/ßcatenin signaling. Biochemical evidence and analyses of mice carrying mutations in the tetraspanin family member, Tspan12, provide evidence that Tspan12 is a Norrin-specific co-receptor that may act by forming a ternary complex with FZD4 (Lai et al, 2017)