Qi Xuan, Pang Qianqian, Wang Jiawei, Zhao Zhen, Wang Ou, Xu Lijun, Mao Jiangfeng, Jiang Yan, Li Mei, Xing Xiaoping, Yu Wei, Xia Weibo
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.
BGI-Shenzhen, Shenzhen, 518083, China.
Calcif Tissue Int. 2017 Aug;101(2):159-169. doi: 10.1007/s00223-017-0269-0. Epub 2017 Apr 7.
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.
骨佩吉特病（PDB）是一种常见的代谢性骨病，其特征是骨吸收增加和骨形成紊乱，可累及单个或多个骨骼部位。尽管PDB的确切病因仍存在争议，但遗传因素被认为在PDB中起重要作用。一些参与破骨细胞分化或功能的基因已被证明与PDB或相关综合征有关，如SQSTM1、TNFRSF11A、TNFRSF11B和ZNF687。多系统蛋白病（MSP）是一种新提出的综合征，包括包涵体肌病（IBM）、PDB、额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS），主要由VCP基因突变引起。2013年，一个新的MSP致病基因被鉴定为hnRNPA2B1基因。这可能部分解释了遗传性PDB特征，然而在已知的PDB致病基因中该特征为阴性突变。我们调查了一个有多个PDB患者的中国家庭，但没有成员表现出IBM、FTD或ALS的症状。对三名患者进行了临床、生化和影像学评估。为了筛查致病突变，对先证者、另一名患者以及该家庭的一名正常个体进行了全外显子测序。结果在两名患者中发现了hnRNPA2B1基因的一个新的杂合错义突变（c.929C>T，p.P310L），随后在所有受影响个体中得到验证。我们在此描述了一个大型PDB家系中hnRNPA2B1基因的一个新的错义突变，该家系成员未表现出多系统蛋白病的其他表现，如IBM、FTD和ALS。
