Six Novel Missense Mutations in the LDL Receptor-Related Protein 5 (LRP5) Gene in Different Conditions with an Increased Bone Density

Abstract

Bone is a dynamic tissue that is subject to the balanced processes of bone formation and bone resorption. Imbalance can give rise to skeletal pathologies with increased bone density. In recent years, several genes underlying such sclerosing bone disorders have been identified. The LDL receptor-related protein 5 (LRP5) gene has been shown to be involved in both osteoporosis-pseudoglioma syndrome and the high-bone-mass phenotype and turned out to be an important regulator of peak bone mass in vertebrates. We performed mutation analysis of the LRP5 gene in 10 families or isolated patients with different conditions with an increased bone density, including endosteal hyperostosis, Van Buchem disease, autosomal dominant osteosclerosis, and osteopetrosis type I. Direct sequencing of the LRP5 gene revealed 19 sequence variants. Thirteen of these were confirmed as polymorphisms, but six novel missense mutations (D111Y, G171R, A214T, A214V, A242T, and T253I) are most likely disease causing. Like the previously reported mutation (G171V) that causes the high-bone-mass phenotype, all mutations are located in the aminoterminal part of the gene, before the first epidermal growth factor-like domain. These results indicate that, despite the different diagnoses that can be made, conditions with an increased bone density affecting mainly the cortices of the long bones and the skull are often caused by mutations in the LRP5 gene. Functional analysis of the effects of the various mutations will be of interest, to evaluate whether all the mutations give rise to the same pathogenic mechanism.

Atherosclerotic Calcification: Wnt Is the Hint

“…These mice did, however, have decreased osteoblast apoptosis, suggesting that the high bone mass phenotype is because of increased osteoblast cell count rather than function. Genomic sequencing of unrelated families with high bone density identified 6 different gain‐of‐function mutations in the LRP5 gene 120. Loss‐of‐function mutations in LRP5 were identified to be associated with osteoporosis 112.…”

Genetic regulation of bone mass and susceptibility to osteoporosis

“…It is important to note, however, that severe osteoporosis and fragility fractures or unusually high bone mass (HBM) can also be an important feature of rare diseases that are primarily genetic in nature and are inherited in a classical Mendelian manner. Such diseases include osteopetrosis, sclerosing bone dysplasias, osteogenesis imperfecta, osteoporosis-pseudoglioma syndrome (OPPS), and osteoporotic syndromes associated with inactivating mutations of the estrogen receptor ␣ and aromatase genes (Bilezikian et al 1998;Janssens and Van Hul 2002;Van Wesenbeeck et al 2003;Balemans et al 2005). Although these diseases are rare, increasing evidence suggests that subtle polymorphic variations in genes that are mutated in these disorders also regulate BMD in the general population.…”

Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation

“…Mutations in LRP5 lead to disorders associated with either low (12)(13)(14) or high bone mass. (15)(16)(17) LRP5 mutations affect bone density by altering osteoblast number and bone accrual. (12,14,15) Controversial data have been published concerning the osteoblastic cell autonomous function of the Lrp5/b-catenin pathway in controlling bone metabolism.…”