Abstract：
Family with sequence similarity 20-member C (FAM20C) is a kinase specific to most of the secreted phosphoproteome. FAM20C has been identified as the causative gene of Raine syndrome, initially characterized by lethal osteosclerosis bone dysplasia. However, since the identification of the cases of nonlethal Raine syndrome characterized by hypophosphatemia rickets, the previous definition of Raine syndrome has become debatable and raised a question about the role of mutations of FAM20C in controversial skeletal manifestation in the two forms of the disease. In this study, we aimed to investigate the influence of FAM20C mutations on skeletogenesis. We developed transgenic mice expressing Fam20c mutations mimicking those associated with human lethal and nonlethal Raine syndrome. The results revealed that transgenic mice expressing the mutant Fam20c found in the lethal (KO;G374R) and nonlethal (KO;D446N) Raine syndrome exhibited osteomalacia without osteosclerotic features. Additionally, both mutants significantly increased the expression of the Fgf23, indicating that Fam20c deficiency in skeletal compartments causes hypophosphatemia rickets. Furthermore, as FAM20C kinase activity catalyzes the phosphorylation of secreted proteomes other than those in the skeletal system, global FAM20C deficiency may trigger alterations in other systems resulting in osteosclerosis secondary to hypophosphatemia rickets. Together, the findings of this study suggest that FAM20C deficiency primarily causes hypophosphatemia rickets or osteomalacia; however, the heterogeneous skeletal manifestation in Raine syndrome was not determined solely by specific mutations of FAM20C. The findings also implicated that rickets or osteomalacia caused by FAM20C deficiency would deteriorate into osteosclerosis by the defects from other systems or environmental impacts.
摘要：
具有序列相似性的20成员C家族（FAM20C）是对大多数分泌的磷酸蛋白质组具有特异性的激酶。FAM20C已被确定为雷恩综合征的致病基因，最初的特点是致命的骨硬化骨发育不良。然而,自从鉴定出以低磷酸盐血症为特征的非致命性雷因综合征病例以来，先前对Raine综合征的定义已成为有争议的,并提出了一个关于FAM20C突变在有争议的两种疾病骨骼表现中的作用的问题.在这项研究中,我们旨在研究FAM20C突变对骨骼形成的影响。我们开发了表达Fam20c突变的转基因小鼠，其模拟与人类致死性和非致死性雷因综合征相关的突变。结果表明，在致死性（KO;G374R）和非致死性（KO;D446N）雷因综合征中发现的表达突变体Fam20c的转基因小鼠表现出无骨硬化特征的骨软化症。此外,两种突变体均显着增加了Fgf23的表达，表明骨骼区室中的Fam20c缺乏会导致低磷酸盐血症。此外，由于FAM20C激酶活性催化骨骼系统以外的分泌蛋白质组的磷酸化，全局性FAM20C缺乏可能会引发其他系统的改变,导致低磷酸盐血症后继发的骨硬化。一起,这项研究的结果表明，FAM20C缺乏主要是导致低磷酸盐血症的病或骨软化症；然而，Raine综合征的异质性骨骼表现并非仅由FAM20C的特异性突变决定.研究结果还暗示，由FAM20C缺乏引起的病或骨软化症会由于其他系统或环境影响的缺陷而恶化为骨硬化。
