Mutant Fam20c knock-in mice recapitulate both lethal and non-lethal human Raine Syndrome

Abstract 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 Fam20cD446N 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 Fam20cD446N knock-in mice displayed hypophosphatemia rickets with the increased Fgf23 and deceased Dmp1 expression, which survived to adulthood. However, there were a few conventional Fam20cD446N knock-in mice died before weaning with the osteosclerotic X-ray radiography. Our results suggested that hypophosphatemia rickets was the predominant phenotype in Fam20c deficient mice, while the lethal osteosclerotic phenotype occasionally took place in the conventional Fam20c mutant mice. This finding implicated that Fam20c deficiency primarily caused hypophosphatemia rickets, but could triggered osteosclerosis in certain context by the alterations in the systems other than skeleton.