title: Thirteen Chinese patients with sporadic Paget's disease of bone: clinical features, SQSTM1 mutation identification, and functional analysis.
abstract: To increase awareness of the rarity of Paget's disease of bone (PDB) in the Chinese population, we characterized the clinical manifestations and features of 13 Chinese sporadic PDB patients. The clinical features of our Chinese PDB patients show similarities with cases reported in Western countries. The most common lesion sites were the pelvis, femur, and tibia; the next most common lesion sites were the spine and skull. Most patients had a higher serum alkaline phosphatase (ALP) level. Treatment with bisphosphonates was effective. In addition, we screened for PDB-causing mutations and performed a functional analysis in an attempt to elucidate the molecular pathogenesis of PDB. A total of 216 persons, including 13 sporadic PDB patients, three unaffected relatives of 1 patient, and 200 healthy donors, were recruited. All eight exons and exon-intron boundaries of the SQSTM1 gene were amplified by polymerase chain reaction (PCR) and directly sequenced. We identified a 53-year-old man who harbored a heterozygous T-to-C transversion at position 1250 in exon 8 (1250T > C), which resulted in a methionine-to-threonine (ATG > ACG) substitution at codon 404 (M404T). The M404T mutant SQSTM1 protein exhibited increased NF-κB activation and drove a significantly increased number of osteoclast-like cells (OLCs) that formed in response to RANKL and an increased number of OLC nuclei. This is the first report of an SQSTM1 genetic mutation that contributes to the pathogenesis of PDB in Chinese patients. These results may partially explain the mechanism by which this SQSTM1 mutation contributes to the pathogenesis of sporadic PDB in Chinese patients.
authors.affiliation: Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors.forename: Jie-Mei
authors.initials: JM
authors.lastname: Gu
authors.forename: Zhen-Lin
authors.initials: ZL
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Hu
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Yue
authors.forename: Yao-Hua
authors.initials: YH
authors.lastname: Ke
authors.forename: Jin-Wei
authors.initials: JW
authors.lastname: He
authors.forename: Yun-Qiu
authors.initials: YQ
authors.lastname: Hu
authors.forename: Miao
authors.initials: M
authors.lastname: Li
authors.forename: Yu-Juan
authors.initials: YJ
authors.lastname: Liu
authors.forename: Wen-Zhen
authors.initials: WZ
authors.lastname: Fu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D044466:Asian People; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004164:Diphosphonates / Q000627:therapeutic use; D005091:Exons; D005260:Female; D006579:Heterozygote; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D010001:Osteitis Deformans / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D017354:Point Mutation; D053245:RANK Ligand / Q000378:metabolism; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004164:Diphosphonates; D016328:NF-kappa B; D053245:RANK Ligand; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C505688:TNFSF11 protein, human; D000469:Alkaline Phosphatase