Chen Mengnan, Sun Dongmei, Yee Siu-Pok, Yuan Zhaoyang, Lin Li, Cui Bing, Wang Yi, Liu Chao, Liu Peihong
Department of Stomatology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, China.
Department of Cell Biology, Health Science Center, University of Connecticut, Farmington, 06030, USA.
BMC Mol Cell Biol. 2025 Jan 2;26(1):1. doi: 10.1186/s12860-024-00526-4.
Inactivation or mutations of FAM20C causes human Raine Syndrome, which manifests as lethal osteosclerosis bone dysplasia or non-lethal hypophosphatemia rickets. However, it is only hypophosphatemia rickets that was reported in the mice with Fam20c deletion or mutations. To further investigate the local and global impacts of Fam20c mutation, we constructed a knock-in allele carrying Fam20c mutation (D446N) found in the non-lethal Raine Syndrome. The Fam20c allele replaced the WT Fam20c by 3.6Kb Col1a1-Cre to get the conditional knock-in mice, and by Hprt-cre to get conventional knock-in mice, respectively.
The radiology, serum biochemistry and immunohistochemistry indicated that all conditional and most conventional Fam20c knock-in mice displayed hypophosphatemic rickets with the increased Fgf23 and deceased Dmp1 expression, which survived to adulthood. However, a few conventional Fam20c knock-in mice died before weaning with the osteosclerotic X-ray radiography, though micro-CT assay displayed a reduced mineral density and increased porosity in the osteosclerotic tibia. Our results suggested that hypophosphatemia rickets was the predominant phenotype in both conditional and conventional Fam20c deficient mice, while the lethal osteosclerotic phenotype occasionally took place in the conventional Fam20c mutant mice.
This finding also implicated that the osteosclerotic features resulting from Fam20c deficiency could be a semblance on the basis of rickets, which is most likely triggered by the alterations in the systems other than skeleton.
FAM20C的失活或突变会导致人类雷恩综合征，表现为致死性骨硬化骨发育异常或非致死性低磷血症佝偻病。然而，在Fam20c缺失或突变的小鼠中仅报道了低磷血症佝偻病。为了进一步研究Fam20c突变的局部和整体影响，我们构建了一个携带在非致死性雷恩综合征中发现的Fam20c突变（D446N）的敲入等位基因。Fam20c等位基因分别通过3.6Kb的Col1a1-Cre取代野生型Fam20c以获得条件性敲入小鼠，并通过Hprt-cre获得传统敲入小鼠。
放射学、血清生化和免疫组化表明，所有条件性和大多数传统Fam20c敲入小鼠均表现出低磷血症佝偻病，伴有Fgf23升高和Dmp1表达降低，这些小鼠存活至成年。然而，少数传统Fam20c敲入小鼠在断奶前死亡，X线摄影显示为骨硬化，尽管显微CT分析显示骨硬化的胫骨矿物质密度降低且孔隙率增加。我们的结果表明，低磷血症佝偻病是条件性和传统Fam20c缺陷小鼠的主要表型，而致死性骨硬化表型偶尔发生在传统Fam20c突变小鼠中。
这一发现还表明，Fam20c缺乏导致的骨硬化特征可能是基于佝偻病的一种表象，很可能是由骨骼以外的系统改变引发的。
