A missense mutation in close proximity of ALS-linked PFN1 mutations causes only early-onset Paget's disease of bone.

Context: Paget's disease of bone (PDB) is a metabolic disorder characterized by abnormal osteoclast activation. Recently, mutations in the PFN1 gene, which encodes Profilin 1, an actin-binding protein controlling actin dynamics and cell movement, have been linked to early-onset PDB. Interestingly, mutations in PFN1 (C71G, T109M, M114T, E117G, G118V, etc.) are associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons.

Objective: To provide insights into the underlying molecular mechanism of early-onset PDB.

Methods: We observed the clinical responses to denosumab in early-onset PDB patients. Additionally, a mouse model carrying the c.335T>C mutation in the Pfn1 gene was generated.

Results: We reported a second Chinese family affected by early-onset PDB with malignant giant cell tumor (GCTs), in which we indentified the same heterozygous missense mutation (c.335T>C/p. L112P) in PFN1 that we have reported previously in another family. Despite its proximity to ALS-linked PFN1 mutations, the PFN1 L112P mutation did not induce ALS in affected individuals. These early-onset PDB patients exhibited a significantly poorer response to denosumab compared to typical PDB patients. The heterozygous mice displayed PDB-like phenotypes, including skeletal deformities and focal osteoclastic lesions with giant osteoclasts, and did not show ALS-like phenotypes. We further show that mutation of Pfn1 leads to enhanced actin ring-like structures at the bone surfaces without affecting NF-κB activation in osteoclast cultures.

Conclusion: The observation of recurrent mutations highlights the causative role of PFN1 (L112P) in early-onset PDB/GCT within the Chinese population and provides insights into the physio-pathological functions of Profilin 1.