Mutation of PFN1 Gene in an Early Onset, Polyostotic Paget-like Disease

Abstract

Context Paget disease of bone (PDB) is a metabolic bone disease whose genetic cause remains unknown in up to 50% of familial patients. Objective Our aim was to investigate the underlying genetic defect in a large pedigree with a severe, early onset, autosomal dominant form of PDB across 3 generations. Methods Whole exome sequencing was performed in affected and unaffected family members, and then mutation screening was replicated in a sample of PDB patients with early-onset, polyostotic PDB. Results We identified a frameshift D107Rfs*3 mutation in PFN1 (encoding for profilin 1, a highly conserved regulator of actin-polymerization and cell motility) causing the truncation of the C-terminal part of the protein. The mutation was also detected in a 17-year-old asymptomatic family member who upon biochemical and radiological analyses was indeed found to be affected. Sequencing of the entire PFN1 coding region in unrelated PDB patients identified the same mutation in 1 patient. All mutation carriers had a reduced response to bisphosphonates, requiring multiple zoledronate infusions to control bone pain and achieve biochemical remission over a long term. In vitro osteoclastogenesis in peripheral blood mononuclear cells (PBMCs) from mutation carriers showed a higher number of osteoclasts with PDB-like features. A similar phenotype was observed upon PFN1 silencing in murine bone marrow-derived monocytes, suggesting that the frameshift PFN1 mutation confers a loss of function in profilin 1 activity that induces PDB-like features in the osteoclasts, likely due to enhanced cell motility and actin ring formation. Conclusions Our findings indicate that PFN1 mutation causes an early onset, polyostotic PDB-like disorder.

Mutations in Profilin 1 Cause Early-Onset Paget's Disease of Bone With Giant Cell Tumors

“…During our manuscript preparation, Italian scientists published work with findings consistent with ours in January 2020 (29) and April 2020 (30) . They reported the same truncating PFN1 mutation c.318_321delTGAC resulting in early-onset severe PDB complicated with osteosarcoma and a germline heterozygous deletion of PFN1 in 4 cases of 218 PDB individuals based on copy number screening, which were not found in our study.…”

“…During our article preparation, Italian scientists published work with findings consistent with ours in January 2020 (29) and April 2020. (30) They reported the same truncating PFN1 mutation c.318_321delTGAC, resulting in early-onset severe PDB complicated with osteosarcoma and a germline heterozygous deletion of PFN1 in 4 cases of 218 PDB individuals based on copy number screening, which were not found in our study. Indeed, since the first description of PDB by Sir James Paget in 1877, it has been clear that the severe and polyostotic form of PDB has the potential for cancer progression in affected bones; the most frequent tumor is osteosarcoma, and the rarest is GCT.…”

Profilin Isoforms in Health and Disease – All the Same but Different

“…Growing numbers of publications, studying patients and/or using cell or animal disease models, link profilins to various diseases: in cancers, PFN1 as well as PFN2 are reported to either act as tumor suppressors or possess oncogenic potential, depending on the studied cancer cell type (for review Pimm et al, 2020). In addition, some studies link PFN1 to a degenerative bone pathology known as Paget Disease (Merlotti et al, 2020;Scotto di Carlo et al, 2020), while others implicate this profilin isoform in vascular inflammation and atherosclerosis (see for review Pae and Romeo, 2014). Particularly, studies on neurological diseases emphasize both the biomedical relevance and the functional diversity of PFN1 and PFN2a isoforms.…”

Update on the pathogenesis and genetics of Paget’s disease of bone

“…Very recently, mutations in the PFN1 gene were separately described in two Italian pedigrees affected with an early onset form of PDB (Scotto di Carlo et al, 2020c;Merlotti et al, 2020) and in two Chinese Han PDB families complicated by GCT (Wei et al, 2021). The same 4-nucleotide deletion giving rise to a frameshift mutation (D107Rfs*3) was found in the Italian families and in one out two Chinese families, as well as in a sporadic Italian PDB case without know family history for the disease.…”