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Thirteen Chinese patients with sporadic Paget’s disease of bone: clinical features, SQSTM1 mutation identification, and functional analysis

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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.

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Acknowledgments

We thank the patients for their participation. We thank Shanghai Genesky Bio-Tech Co., Ltd., for their help with gene identification. We thank Dr. X.L. Cai for his help in the cellular biology experiment.

Conflict of interest

The authors have no conflicts of interest.

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Authors and Affiliations

  1. 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

    Jie-mei Gu, Zhen-Lin Zhang, Hao Zhang, Wei-wei Hu, Chun Wang, Hua Yue, Yao-hua Ke, Jin-wei He, Yun-qiu Hu, Miao Li, Yu-juan Liu & Wen-zhen Fu

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  1. Jie-mei Gu
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  2. Zhen-Lin Zhang
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  12. Wen-zhen Fu
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Correspondence to Zhen-Lin Zhang.

Additional information

The study was supported by the National Natural Science Foundation of China (NSFC) (No. 30771019, 30800387, 81070692, 81170803); Shanghai Excellent Academic Leaders Plan (XBR2011014); Shanghai Science and Technology Development Fund (Project No. 08411963100 and 11ZR1427300); and Shanghai Rising-Star program (11QA1404900).

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Gu, Jm., Zhang, ZL., Zhang, H. et al. Thirteen Chinese patients with sporadic Paget’s disease of bone: clinical features, SQSTM1 mutation identification, and functional analysis. J Bone Miner Metab 30, 525–533 (2012). https://doi.org/10.1007/s00774-012-0352-6

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  • DOI: https://doi.org/10.1007/s00774-012-0352-6

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