Raine syndrome is caused by mutations in FAM20C, which had been reported to encode a secreted component of bone and teeth. We found that FAM20C encodes a Golgi-localized
protein kinase, distantly related to the Golgi-localized
kinase Four-jointed. Drosophila also encode a Golgi-localized
protein kinase closely related to FAM20C. We show that FAM20C can phosphorylate secreted
phosphoproteins, including both
Casein and members of the SIBLING
protein family, which modulate biomineralization, and we find that FAM20C phosphorylates a biologically active
peptide at
amino acids essential for inhibition of biomineralization. We also identify autophosphorylation of FAM20C, and characterize parameters of FAM20C's
kinase activity, including its Km, pH and
cation dependence, and substrate specificity. The biochemical properties of FAM20C match those of an enzymatic activity known as Golgi
casein kinase. Introduction of point mutations identified in
Raine syndrome patients into recombinant FAM20C impairs its normal localization and
kinase activity. Our results identify FAM20C as a
kinase for secreted
phosphoproteins and establish a biochemical basis for
Raine syndrome.