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.

中文翻译：

---

LRP6 的新变异与异常和严重的临床表现相关：病例报告

低密度脂蛋白受体相关蛋白6（LRP6）是Wnt信号通路的共同受体，在胚胎和出生后发育过程中的各种生物活动中发挥着重要作用。LRP6与罕见疾病异常相关，并且总是与常染色体显性遗传有关。在此，我们报告了一种与骨骼异常和少牙相关的高骨量家族表型，但也与持续性左上腔静脉、腹股沟疝、肝囊肿、后颅窝异常和生殖器畸形有关。分子分析揭示了受影响个体中的一种新杂合变异 NM_002336.2: c.724T>C, p.(Trp242Arg)。该变体位于第一个 β-推进剂基序中LRP6，其中硬化蛋白（索斯特）和迪克科普夫1（丹麦克朗1）， 二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数据，这种变体扭曲了索斯特和丹麦克朗1，从而导致参与成骨细胞分化的Wnt信号通路过度激活。这种新的杂合变体LRP6其作用的基础是LRP6骨骼和牙齿疾病以及可能的心脏、大脑和生殖器发育。