研究低密度脂蛋白受体相关蛋白5(LRP5)基因突变对骨,并打开我们对LRP5和Wnt通路对骨量调节的看法。包括三名骨密度增加或骨皮质增厚的患者。30岁的人，22岁和50岁的男人,分别。后两名患者是同一家庭的儿子和父亲。详细评估了骨X射线的特征。检测到骨转换标志物，如1型前胶原氨基末端肽（P1NP），碱性磷酸酶(ALP),和1型胶原羧基末端肽(β-CTX)。双能X线骨密度仪（DXA）用于测量患者腰椎和股骨近端的骨密度（BMD）。靶向下一代测序(NGS)技术用于检测致病基因突变,经Sanger测序进一步验证。此外，通过文献复习,对已报道的LRP5功能获得突变患者的基因突变谱和表型特征进行总结.首例患者的主要特点是头痛,面瘫,高BMD（腰椎1-4：1.877g/cm2，Z评分：5.8；全髋关节：1.705g/cm2，Z评分：5.7），P1NP（87.0ng/mL）和β-CTX（0.761ng/mL）水平略有增加，骨皮质增厚，尤其是颅骨穹顶.后两名患者表现出下颌骨的增大和旅行的骨性突出。X线片显示颅骨皮质和长骨增厚。骨转换标志物和BMD正常。3例LRP5基因均携带新型错义突变,这是外显子3的突变（c.586T>G，p.Trp196Gly）的第一位患者，和外显子20的突变（c.4240C>A，p.Arg1414Ser）后两名患者。结合文献报道,在33个家庭的113例患者中,共检测到19例LRP5功能获得突变.热点突变包括c.724G>A，c.512G>T和c.758C>T。此外，LRP5外显子3的突变可能导致严重的表型.LRP5功能获得突变可导致罕见的常染色体显性骨硬化I型（ADOI），其特征是骨量增加和骨皮质增厚。对Wnt通路的深入研究将有助于发现骨量调节的重要机制。
To study the effects of low-density lipoprotein receptor-related protein 5 (LRP5) gene mutations on bone, and to open up our view of LRP5 and Wnt pathways on bone mass regulation. Three patients with increased bone mineral density or thickened bone cortex were included, who were 30-year-old, 22-year-old and 50-year-old men, respectively. The latter two patients were son and father of a same family. The characteristics of bone X-rays were evaluated in detail. Bone turnover markers were detected, such as procollagen type 1 amino-terminal peptide (P1NP), alkaline phosphatase (ALP), and type 1 collagen carboxyl terminal peptide (β-CTX). Dual energy X-ray absorptiometry (DXA) was used to measure the bone mineral density (BMD) at lumbar spine and proximal femur of the patients. The targeted next-generation sequencing (NGS) technology was used to detect pathogenic gene mutations, which were further verified by Sanger sequencing. Moreover, the gene mutation spectrum and phenotypic characteristics of reported patients with LRP5 gain-of-function mutations were summarized by reviewing the literature. The main characteristics of the first patient were headache, facial paralysis, high BMD (lumbar vertebrae 1-4: 1.877 g/cm2, Z-score: 5.8; total hip: 1.705 g/cm2, Z-score: 5.7), slightly increased P1NP (87.0 ng/mL) and β-CTX (0.761 ng/mL) level, and with thickened bone cortex, especially the cranial vault. The latter two patients showed enlargement of the mandible and enlarged osseous prominence of the tours palatinus. X-rays showed that the bone cortex of skull and long bones were thickened. The bone turnover markers and BMD were normal. All three cases carried novel missense mutations in LRP5 gene, which were mutation in exon 3 (c.586 T > G, p.Trp196Gly) of the first patient, and mutation in exon 20 (c.4240C > A, p.Arg1414Ser) of the latter two patients. Combined with the reported literature, a total of 19 gain-of-function mutations in LRP5 were detected in 113 patients from 33 families. Hotspot mutations included c.724G > A, c.512G > T and c.758C > T. Furthermore, mutations in the exon 3 of LRP5 may cause severe phenotypes. LRP5 gain-of-function mutations can lead to rare autosomal dominant osteosclerosis type Ι (ADO Ι), which was characterized by increased bone mass and thickened bone cortex. In-depth research on the Wnt pathway will be benefit for discovering important mechanisms of bone mass regulation.
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