Paget disease of bone (PDB) is a common metabolic bone disease characterized by increased bone resorption and disorganized bone formation which can affect single or multiple sites of bone. Although the exact cause of PDB is still controversial, genetic factor is considered to play an important role in PDB. The causative gene of classical PDB was identified as Q8STM1 gene. Familial expansile osteolysis caused by the mutation of TNFRSF11A(RANKL) gene and juvenile PDB caused by mutation of TNFRSF11B(OPG) gene have similar pagetic pathology of bone. Multisystem proteinopathy (MSP), a newly proposed syndrome including inclusion-body myopathy (IBM), PDB, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), is mainly caused by mutation in VCP gene. In 2013, a new casual gene for MSP was identified as hnRNPA2B1 gene. This may give part explain to the inherited PDB which is negative for mutation in TNFRSF11A/B and Q8STM1 gene. We investigate a Chinese family with multiple affected individuals with Paget disease of bone but no member shows symptoms of IBM, FTD or ALS. Three patients were evaluated clinically, biochemically and radiographically. To screen for the responsible mutation, whole-exom sequencing was conducted in the proband, another patient and a normal individual from the family and revealed a novel heterozygous missense mutation of hnRNPA2B1 gene (c.929C>T, p.P310L) in the two patients and then verified in all the affected individuals. We describe a novel missense mutation in hnRNPA2B1 gene in a big pedigree affected with Paget disease of bone whose members do not present other manifestation of multisystem proteinopathy, such as IBM, FTD and ALS.
14 - 17 May 2016
European Calcified Tissue Society