Intracranial calcification in Fam20c-deficient mice recapitulates human Raine syndrome

Neurosci Lett. 2023 Apr 1:802:137176. doi: 10.1016/j.neulet.2023.137176. Epub 2023 Mar 11.


FAM20C (family with sequence similarity 20-member C) is a protein kinase that phosphorylates secretory proteins, including the proteins that are essential to the formation and mineralization of calcified tissues. FAM20C loss-of-function mutations cause Raine syndrome in humans, characterized by generalized osteosclerosis, distinctive craniofacial dysmorphism, along with extensive intracranial calcification. Our previous studies revealed that inactivation of Fam20c in mice led to hypophosphatemic rickets. In this study, we examined the expression of Fam20c in the mouse brain and investigated brain calcification in Fam20c-deficient mice. Reverse transcription polymerase chain reaction (RT-PCR), Western-blotting and in situ hybridization analyses demonstrated the broad expression of Fam20c in the mouse brain tissue. X-ray and histological analyses showed that the global deletion of Fam20c (mediated by Sox2-cre) resulted in brain calcification in mice after postnatal 3 months and that the calcifications were bilaterally distributed within the brain. There was mild perifocal microgliosis as well as astrogliosis around calcospherites. The calcifications were first observed in the thalamus, and later in the forebrain and hindbrain. Furthermore, brain-specific deletion (mediated by Nestin-cre) of Fam20c in mice also led to cerebral calcification at an older age (postnatal 6 months), but no obvious skeletal or dental defects. Our results suggest that the local loss of FAM20C function in the brain may directly account for intracranial calcification. We propose that FAM20C plays an essential role in maintaining normal brain homeostasis and preventing ectopic brain calcification.

Keywords: Brain calcification; FAM20C; Protein kinase; Raine syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcinosis* / genetics
  • Calcium-Binding Proteins
  • Casein Kinase I / genetics
  • Casein Kinase I / metabolism
  • Cleft Palate* / genetics
  • Exophthalmos* / genetics
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Humans
  • Mice
  • Microcephaly* / genetics
  • Osteosclerosis* / diagnostic imaging
  • Osteosclerosis* / genetics


  • Extracellular Matrix Proteins
  • FAM20C protein, human
  • Casein Kinase I
  • FAM20C protein, mouse
  • Calcium-Binding Proteins

Supplementary concepts

  • Raine syndrome