Investigations of a kindred with high spinal bone mass, but no other syndromic features, revealed a locus on chromosome 11q12-q13 (Johnson et al., 1997) where gain-of-function mutations in LRP5 have been identified (Little et al., 2002). The same mutation has also been found in a kindred with high bone mass that also exhibited entrapment neuropathies, squaring of the jaw, and hard palate abnormalities (Boyden et al., 2002). Additional LRP5 mutations (and polymorphisms) have been found in other forms of osteopetrosis including van Buchem's disease (Van Wesenbeeck et al., 2003). The phenotypic differences in disorders seemingly related to LRP5 raise the possibility that there are other modifying genes and/or environmental factors at work (Little et al., 2002). A candidate for a modifying gene is TCIRG1/ATP6i, which is in the same region as LRP5 and is known to affect bone homeostasis.
LRP5 activity is controlled by an antagonist known as Dickkopf (Dkk) (Figure 27.1). Dkk-family gene products can bind with high affinity to LRPs and prevent Wnt signaling. The LRP5 mutation associated with high bone mass allows it to escape inhibition by Dkk, and overstimulate osteoblast proliferation and differentiation, thus accounting for the phenotype (Boyden etal., 2002). Osteoporosis pseudoglioma, which has a low bone mass phenotype, is due to inactivating mutations. LRP5 mutations are of considerable importance not only in terms of understanding the pathophys-iology of bone mass, but also since the activating mutants may prove to be useful as biologic agents for stimulating bone formation (Patel and Karsenty, 2002).
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