FAM20C Overview: Classic and Novel Targets, Pathogenic Variants and Raine Syndrome Phenotypes

Abstract

FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.

Fam20C in Human Diseases: Emerging Biological Functions and Therapeutic Implications

“…RS is a bone dysplasia with characteristic features of generalized osteosclerosis, craniofacial anomalies, and intracerebral calcifications ( Vishwanath et al, 2014 ), which is caused by mutations of Fam20C. Hitherto, 42 variants of Fam20C gene have been summarized to be responsible for RS, and they cause either lethal or non-lethal cases ( Palma-Lara et al, 2021 ). For example, mutations of FAM20C gene (MIM *611061) are reported to impair splicing process, leading to the functional loss of proteins and causing disease phenotype ( Simpson et al, 2007 ).…”

“…Fam20C, this kinase, and its family members Fam20A and Fam20B define a new family of secretory proteins that collectively regulate a diverse network of secretory pathway components ( Palma-Lara et al, 2021 ). As the most widely studied member of the Fam20 family, Fam20C is a secreted protein with kinase activity.…”

Comparative N-Glycoproteomic Investigation of Eggshell Cuticle and Mineralized Layer Proteins

“…Interestingly, the PPI network indicated that fam20C domain-containing protein (A0A1D5NTR9) interacted with 15 proteins. Moreover, BLASTP () showed that this protein sequence was highly similar to its human homologue (75.64%), which binds calcium ions and regulates bone mineralization in mammals. − In this study, the sequences near the glycosites of fam20C domain-containing protein were identical to the human sequences; therefore, this protein may have similar functions and effects during eggshell mineralization. Specific glycosylation of ovotransferrin (OVT, A0A1D5NZF8) occurred at N650 in ECL, and the protein interacted with 13 neighbors.…”

Compound heterozygous FAM20C gene variants in a patient with severe Raine syndrome: a case report

“…Besides its role in bone tissues, FAM20C is also essential in non-bone tissues, acting on neuropeptides of secretory pathways in nervous and endocrine systems, vascular calcifications through sortilin1, and metabolism through its targets PCSK7 and PCSK9. While some suggest its potential role in redox homeostasis, clotting, and salivary glands, no clinical evidence supports it ( Palma-Lara, I., et al, 2021 ). According to available information, 53 distinct variations (identified as pathogenic by ClinVar) have been documented in cases of Raine syndrome, encompassing splicing defects, frameshift, missense, non-sense mutations (causing truncated proteins), and chromosomal rearrangements, both lethal and non-lethal.…”