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LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low-Density Lipoprotein Receptor-Related Protein 6. | LitMetric

AI Article Synopsis

  • - Wnt/-catenin signaling in osteoblasts is crucial for bone development and health, where Wnt proteins bind to LRP5 or LRP6 receptors to promote bone formation; however, certain proteins like sclerostin and dickkopf1 can inhibit this process by disrupting the receptor complex.
  • - Mutations in the LRP5 and LRP6 genes, identified in several families, prevent the inhibitory effects of sclerostin and dickkopf1, leading to high bone mass disorders known as LRP5 and LRP6 high bone mass (HBM).
  • - A case study of a large family with a novel LRP6 mutation showed that despite high bone density and certain skeletal traits, the

Article Abstract

Osteoblast Wnt/-catenin signaling conditions skeletal development and health. Bone formation is stimulated when on the osteoblast surface a Wnt binds to low-density lipoprotein receptor-related protein 5 (LRP5) or 6 (LRP6), in turn coupled to a frizzled receptor. Sclerostin and dickkopf1 inhibit osteogenesis if either links selectively to the first β-propeller of LRP5 or LRP6, thereby disassociating these cognate co-receptors from the frizzled receptor. Sixteen heterozygous mutations identified since 2002 within and three heterozygous mutations identified since 2019 within prevent this binding of sclerostin or dickkopf1 and account for the exceptionally rare, but highly instructive, autosomal dominant disorders called LRP5 and LRP6 high bone mass (HBM). Herein, we characterize LRP6 HBM in the first large affected family. Their novel heterozygous missense mutation (c.719C>T, p.Thr240Ile) was present in two middle-aged sisters and three of their sons. They considered themselves healthy. Their broad jaw and torus palatinus developed during childhood and, contrary to the two previous reports of LRP6 HBM, the appearance of their adult dentition was unremarkable. Skeletal modeling, defined radiographically, supported classification as an endosteal hyperostosis. Areal bone mineral density (g/cm) of the lumbar spine and total hip featured accelerated increases reaching -scores of ~ +8 and +6, respectively, although biochemical markers of bone formation were normal. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10097642PMC
http://dx.doi.org/10.1002/jbm4.10717DOI Listing

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