Abstract：
Low-density lipoprotein receptor-related protein 6 (LRP6) is a co-receptor of the Wnt signaling pathway, which plays an essential role in various biological activities during embryonic and postnatal development. LRP6 is exceptionally associated with rare diseases and always with autosomal dominant inheritance. Here we report a familial phenotype of high bone mass associated with skeletal anomalies and oligodontia but also persistent left superior vena cava, inguinal hernia, hepatic cysts, abnormal posterior fossa and genital malformations. Molecular analysis revealed a novel heterozygous variant, NM_002336.2: c.724T>C, p.(Trp242Arg), in affected individuals. This variant is located in the first β-propellant motif of LRP6, to which sclerostin (SOST) and dickkopf1 (DKK1), two LRP6 co-receptor inhibitors and various Wnt ligands bind. According to the literature and integrating data from structural analysis, this variant distorts the binding of SOST and DKK1, thus leading to overactivation of Wnt signaling pathways involved in osteoblast differentiation. This novel heterozygous variant in LRP6 underlies the role of LRP6 in skeletal and dental disorders as well as, probably, cardiac, cerebral and genital developments.
摘要：
低密度脂蛋白受体相关蛋白6(LRP6)是Wnt信号通路的共受体,在胚胎和出生后的各种生物活动中起着至关重要的作用。LRP6与罕见疾病异常相关，并且始终与常染色体显性遗传有关。在这里，我们报告了与骨骼异常和少突相关的高骨量的家族表型，以及持续的左上腔静脉，腹股沟疝,肝囊肿,异常后颅窝和生殖器畸形。分子分析揭示了一种新的杂合变体，NM_002336.2:c.724T>C,p.(Trp242Arg),在受影响的个人。此变体位于LRP6的第一个β-推进剂基序中，其中硬化蛋白（SOST）和dickkopf1（DKK1），两种LRP6共受体抑制剂和各种Wnt配体结合。根据文献和整合结构分析的数据，这种变异扭曲了SOST和DKK1的结合,从而导致参与成骨细胞分化的Wnt信号通路过度激活.LRP6中的这种新型杂合变体是LRP6在骨骼和牙齿疾病中的作用基础，可能,心脏,大脑和生殖器发育。
