title: Familial Early-Onset Paget's Disease of Bone Associated with a Novel hnRNPA2B1 Mutation.
abstract: Paget disease of bone (PDB) is a common metabolic bone disease characterized by increased bone resorption and disorganized bone formation which affect single or multiple sites of bones. Although the exact cause of PDB is still controversial, genetic factors are considered to play an important role in PDB. Several genes involved in the differentiation or function of osteoclast were shown to be associated with PDB or related syndrome such as SQSTM1, TNFRSF11A, TNFRSF11B, and ZNF687. 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 partly account for the inherited PDB traits which is however negative for mutation in already known causative PDB genes. We investigated a Chinese family with multiple affected individuals with PDB, but none of the members showed symptoms of IBM, FTD, or ALS. Three patients were evaluated clinically, biochemically, and radiographically. To screen for the responsible mutation, whole-exome sequencing was conducted in the proband, another patient, as well as a normal individual from the family. This revealed a novel heterozygous missense mutation of hnRNPA2B1 gene (c.929C>T, p. P310L) in the two patients which was then verified in all affected individuals. We describe here a novel missense mutation in hnRNPA2B1 gene in a large pedigree affected with PDB with members who do not present other manifestations of multisystem proteinopathy, such as IBM, FTD, and ALS.
authors.affiliation: Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, Beijing, 100730, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Qi
authors.affiliation: Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, Beijing, 100730, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Pang
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China.|Binhai Genomics Institute, BGI-Tianjin, BGI-shenzhen, Tianjin, 300308, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, Beijing, 100730, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, Beijing, 100730, China.
authors.forename: Ou
authors.initials: O
authors.lastname: Wang
authors.affiliation: Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, Beijing, 100730, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xu
authors.affiliation: Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, Beijing, 100730, China.
authors.forename: Jiangfeng
authors.initials: J
authors.lastname: Mao
authors.affiliation: Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, Beijing, 100730, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, Beijing, 100730, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, Beijing, 100730, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China. asan@genomics.cn.|Binhai Genomics Institute, BGI-Tianjin, BGI-shenzhen, Tianjin, 300308, China. asan@genomics.cn.
authors.lastname: Asan
authors.affiliation: Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, Beijing, 100730, China. xiaweibo@medmail.com.cn.
authors.forename: Weibo
authors.initials: W
authors.lastname: Xia
mesh_terms: D000328:Adult; D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D020022:Genetic Predisposition to Disease; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010001:Osteitis Deformans / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D000074405:Valosin Containing Protein / Q000235:genetics
chemical_list: D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C439768:hnRNP A2; D000074405:Valosin Containing Protein
keywords: HnRNPA2B1; MSP; Multisystem proteinopathy; PDB; Paget disease