A novel VCP mutation as the cause of atypical IBMPFD in a Chinese family
A novel VCP mutation as the cause of atypical IBMPFD in a Chinese family
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一种新的 VCP 突变导致中国家庭中非典型 IBMPFD
DOI：
10.1016/j.bone.2012.09.012
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发表时间：
2013-01-01
期刊：
影响因子：
4.1
通讯作者：
Zhang, Zhen-Lin
中科院分区：
文献类型：
--
作者：
Gu, Jie-Mei;Ke, Yao-Hua;Zhang, Zhen-Lin
前言：包涵体肌病是一种罕见的常染色体显性遗传病(MIM 605382)。IBMPFD是由编码含有Valosin的蛋白(VCP)的基因突变引起的。我们调查了一个中国家庭，其中多名成员被诊断为PDB，并患有四肢无力。然而，这个家庭没有成员被诊断为FTD。我们做出了PDB的初步诊断，但未能在任何患者中发现SQSTM1突变。本研究采用全外显子组测序的方法对影响中国男性先证者的致病基因突变进行分析。材料和方法：共254例受试者，包括1名56岁男性先证者、4名先证者和另外9名家系成员，以及240名健康献血者，提取基因组DNA。对5例患者(II13、II4、II5、II8、II9)的全部8个外显子和外显子-内含子边界进行了聚合酶链式反应(PCR)扩增和直接测序。通过全外显子组测序，我们确定了VCP中的一个新突变为致病突变。我们用Sanger测序法对所有254名受试者的启动子和VCP的编码区进行了测序，证实了这一结果。结果：用Sanger直接测序法检测的5例患者中没有发现SQSTM1基因突变。然而，通过全外显子测序，我们在中国男性先证者中发现了VCP基因外显子3(p.Gly97Glu)的一个新的错义突变。这一突变通过桑格测序得到证实。先证者、四个受影响的人和三个未受影响的人携带这种突变。我们能够正确诊断出不典型的IBMPFD患者。对VCP蛋白中P.Gly97Glu突变的结构分析表明，受影响的氨基酸位于蛋白质的界面。结论：这是中国家系中首次报道的IBMPFD家系。在一个中国家系中发现了一种新的VCP突变，该突变是导致不典型IBMPFD的原因。我们的发现证实了VCP基因突变可能是IBMPFD的致病原因之一。(C)2012 Elsevier Inc.保留所有权利。
Introduction: Inclusion-body myopathy (IBM) with Pager's disease of bone (PDB) and frontotemporal dementia (FTD), designated as IBMPFD, is a rare, autosomal dominant disorder (MIM 605382). IBMPFD is caused by mutations in the gene that encode valosin-containing protein (VCP). We investigated a Chinese family in which multiple members were diagnosed with PDB and suffered from weakness of the limbs. However, no members of this family were diagnosed with FTD. We made a preliminary diagnosis of PDB, but failed to identify an SQSTM1 mutation in any of the patients. We used whole-exome sequencing to identify the pathogenic gene mutation affecting the Chinese male proband.Materials and methods: Altogether, 254 subjects, including one 56-year-old male proband, four affected, related individuals and additional nine family members from a non-consanguineous Chinese family, and 240 healthy donors were recruited and genomic DNA was extracted. All eight exons and the exon-intron boundaries of the SQSTM1 gene were amplified by polymerase chain reaction (PCR) and directly sequenced in five patients (II13, II4, II5, II8, II9). Using whole-exome sequencing, we identified a novel mutation in VCP as the disease-causing mutation. We confirmed the result by sequencing a 500-bp region of the promoter and the coding region of VCP in all 254 of the participants using Sanger sequencing.Results: No mutation in the SQSTM1 gene was identified in the five patients examined using direct Sanger sequencing. However, through whole-exome sequencing we were able to identify a novel missense mutation in exon 3 of the VCP gene (p.Gly97Glu) in the Chinese male proband. This mutation was confirmed using Sanger sequencing. The proband, four affected individuals and three unaffected individuals carried this mutation. We were able to correctly diagnose the patients with atypical IBMPFD. Structural analysis of the p.Gly97Glu mutation in the VCP protein showed that the affected amino-acid is located in the interface of the protein. This abnormality may therefore interfere with protein function.Conclusions: This is the first report of a family from China with IBMPFD. A novel VCP mutation was found as the cause of atypical IBMPFD in a Chinese family. Our findings confirm that VCP gene mutations can be a pathogenic cause of IBMPFD. (c) 2012 Elsevier Inc. All rights reserved.