Akademik Veri Yönetim Sistemi
HUMAN MOLECULAR GENETICS, 2025 (SCI-Expanded, Scopus)
Raine syndrome (RNS) is an autosomal recessive neonatal osteosclerotic bone dysplasia that usually results in death in the postnatal period. Patients present with abnormal craniofacial features and widespread periosteal osteosclerosis affecting the ribs, skull, and long bones. Nonlethal forms of RNS have recently been reported. Biallelic mutations in the FAM20C gene, which encodes a Golgi serine/threonine protein kinase that phosphorylates secretory pathway proteins, are responsible for RNS. In this study, we examined a Turkish family consisting of three patients by exome sequencing and found that the homozygous c.1071A > G transition at the second-to-last position of the 5 ' end of exon 5 gave rise to a synonymous variant (p.P357P) in FAM20C. Subsequent mRNA (cDNA) sequencing of FAM20C showed that the c.1071A > G substitution disrupted the splice junction and directed the splicing to a new location in intron 5, resulting in an in-frame 12 amino acid insertion into the protein. FAM20C is a serine/threonine protein kinase that localizes to the Golgi apparatus by forming a homo- or hetero-dimer and/or is secreted from the cell to phosphorylate secretory proteins. Functional analysis showed that the identified insertion did not disrupt either homo- or hetero-dimerization of the FAM20C protein. However, this variant protein failed to localize properly to the Golgi apparatus and exhibited poor secretion from the cell. All these findings suggest that the identified variant causing the 12 amino acid insertion is responsible for the nonlethal form of RNS in the family and provides mechanistic insight into the molecular pathogenesis of RNS.