Mutations in FAM20C also identified in non‐lethal osteosclerotic bone dysplasia

Abstract

Raine syndrome is an osteosclerotic bone dysplasia, which has proved to be lethal within the first few weeks of life in all the reported cases to date. We recently identified a chromosomal rearrangement and telomeric microdeletion in a patient with Raine syndrome and subsequently identified mutations in the FAM20C gene, located within the deleted region, in six additional Raine syndrome cases. The phenotype of Raine syndrome in the cases examined was remarkably consistent with generalized osteosclerosis of all bones, periosteal bone formation, characteristic facial phenotype and lethal within the first few weeks of life. In the current study, we have identified two unrelated individuals who presented at birth with a sclerosing bone dysplasia with features very similar to those in Raine syndrome but who survived infancy and are now aged 8 and 11 years, respectively. Mutations in FAM20C, consistent with autosomal recessive inheritance, were identified in both cases. In the first case, a homozygous non-synonymous mutation in exon 7 (1309G>A D437N) was identified, and in the second case, compound heterozygosity for non-synonymous mutations in exon 2 (731T>A I244N) and in exon 3 (796G>A G266R) was revealed. Raine syndrome has been previously considered to be a neonatal lethal condition. However, the identification of mutations in these two patients confirms a broader phenotypic spectrum and that mutation of FAM20C does not always lead to the infantile lethality previously seen as a prerequisite for Raine syndrome diagnosis.

Crystal structure of the Golgi casein kinase

“…3A). The importance of this interaction is underscored by the fact that mutation of this Asp to Asn causes Raine syndrome (Table S2) (17). This substitution is predicted to destabilize the conformation of the catalytic segment and alter both the stability and activity of the kinase.…”

“…Furthermore, mutations in FAM20C cause Raine syndrome, a deadly osteosclerotic bone dysplasia characterized by generalized osteosclerosis, ectopic calcifications, and characteristic facial features (14-16). Most individuals with Raine syndrome die within a few weeks after birth; however, nonlethal cases with dental abnormalities and clinical features of hypophosphatemia have been reported (17,18). Loss of Fam20C in mice also results in severe bone and tooth anomalies, as well as hypophosphatemia (19)(20)(21).…”

Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis

“…Subsequently, mutations in the FAM20C gene were found to be responsible for this disorder (10), and recent reports suggest a broader phenotypic spectrum for individuals with FAM20C mutations because some patients survive infancy (12,34). Notably, Rafaelsen et al (12) identified a novel missense mutation in Fam20C that substituted Thr 268 with a Met in two compound heterozygous brothers who had elevated serum intact FGF23 and hypophosphatemia.…”

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

“…30 Some cases have shown biochemical findings consistent with hypophosphatemic rickets. 87 So far, all identified Raine syndrome mutations involve the evolutionarily conserved amino acids located within the CCD of FAM20C. Since the original submission of this article, FAM20C has been identified as a kinase that phosphorylates proteins in the secretory pathways, including secretory calcium binding phosphoproteins (SCPP), that have a high affinity for calcium and regulate biomineralization.…”

“…86 However, recent findings have shown a much wider clinical spectrum associated with FAM20C mutations in humans than the classic neonatal lethal presentation. 87 Nonlethal forms of Raine syndrome are characterized by mineralization defects, including generalized osteosclerosis, small teeth with enamel dysplasia, and ectopic calcifications of the intervertebral disks and kidneys. 30 Some cases have shown biochemical findings consistent with hypophosphatemic rickets.…”