Whyte Michael P, Mumm Steven, Baker Jonathan C, Zhang Fan, Sedighi Homer, Duan Shenghui, Cundy Tim
Division of Bone and Mineral Diseases, Department of Internal Medicine Washington University School of Medicine at Barnes-Jewish Hospital St. Louis MO USA.
Center for Metabolic Bone Disease and Molecular Research Shriners Hospitals for Children - St. Louis St. Louis MO USA.
JBMR Plus. 2023 Mar 2;7(4):e10717. doi: 10.1002/jbm4.10717. eCollection 2023 Apr.
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.
成骨细胞的Wnt/β-连环蛋白信号传导调控骨骼发育与健康。当Wnt在成骨细胞表面与低密度脂蛋白受体相关蛋白5（LRP5）或6（LRP6）结合时，会刺激骨形成，而LRP5或6又与卷曲受体相连。如果硬化蛋白或Dickkopf1选择性地与LRP5或LRP6的第一个β-螺旋桨结合，就会抑制骨生成，从而使这些同源共受体与卷曲受体解离。自2002年以来在LRP5中鉴定出16个杂合突变，自2019年以来在LRP6中鉴定出3个杂合突变，这些突变阻止了硬化蛋白或Dickkopf1的这种结合，导致了极为罕见但极具启发性的常染色体显性疾病，即LRP5和LRP6高骨量（HBM）疾病。在此，我们对首个大型患病家族中的LRP6 HBM进行了特征描述。他们的新型杂合LRP6错义突变（c.719C>T，p.Thr240Ile）存在于两名中年姐妹及其三个儿子中。他们自认为身体健康。她们宽阔的下颌和腭隆突在童年时期就已形成，与之前两份关于LRP6 HBM的报告不同，她们成年后的牙列外观并无异常。通过X线影像学定义的骨骼建模支持将其归类为骨内膜增生症。腰椎和全髋的骨面积密度（g/cm²）加速增加，Z值分别达到约+8和+6，尽管骨形成的生化指标正常。© 2023作者。由Wiley Periodicals LLC代表美国骨与矿物质研究学会出版。
