Fig. 6. Schematic representation of possible LRP6 domains involved in Wnt, Dkk and Wise binding, and of LRP5 mutations in human diseases. (Top) LRP6. Domains involved in Wnt, Wise and Dkk1 binding have only been mapped for LRP6 and are marked. Whether SOST binds LRP5/LRP6 is unknown. (Bottom) LRP5 mutations associated with osteoporosis-pseudoglioma (OPPG) syndrome, autosomal-dominant familial exudative vitreoretinopathy (FEVR), and various high bone density diseases are shown in red, purple and green, respectively. Arrows indicate mutation locations. *, nonsense mutation; fs, frame-shift mutation. OPPG is autosomal recessive, and the nine mutations indicated are from homozygous offspring of consanguineous families (Gong et al., 2001). FEVR discussed here is an autosomal-dominant form, possibly due to haploinsufficiency. Whether the three OPPG and three FEVR missense mutations (italicized) are loss-of-function mutations remains to be tested. T1449fs# in FEVR should be treated as hypothetical because the mutation occurs at a splice donor site in an intron. Note that the mutations associated with high bone density diseases, which are autosomal dominant because of probable `gain of function', are all missense mutations and are clustered in the first YWTD ß-propeller domain. SP, signal peptide; TM, transmembrane domain.