Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein
Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein
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DOI：
10.1038/ng1332
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发表时间：
2004-04-01
期刊：
影响因子：
30.8
通讯作者：
Kimonis, VE
中科院分区：
文献类型：
--
作者：
Watts, GDJ;Wymer, J;Kimonis, VE
包涵体肌病与Paget病相关的骨骼和额颞部痴呆(IBMPFD)是一种显性进行性疾病，位于染色体9p21.1-p12。我们用候选基因的方法调查了13个9号染色体连锁的IBMPFD家系。我们发现，在所有61名患者中，包含Valosin的蛋白(VCP，AAA-ATPase超家族成员之一)编码基因有6个错义突变。单倍型分析表明，在受影响的两个家庭中，来自两个独立的北美家族的两个创始人的后裔导致IBMPFD的比例类似于50%。VCP与多种细胞活动有关，包括细胞周期调控、膜融合和泛素-蛋白酶体降解途径。VCP是IBMPFD的致病因子，对其他包涵体疾病，包括肌肉病变、痴呆和Paget病(PDB)具有重要意义，因为它可能定义一种新的常见的基于泛素的病理途径。
Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome 9p21.1-p12. We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach. We found six missense mutations in the gene encoding valosin-containing protein (VCP, a member of the AAA-ATPase superfamily) exclusively in all 61 affected individuals. Haplotype analysis indicated that descent from two founders in two separate North American kindreds accounted for IBMPFD in similar to 50% of affected families. VCP is associated with a variety of cellular activities, including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation pathway. Identification of VCP as causing IBMPFD has important implications for other inclusion-body diseases, including myopathies, dementias and Paget disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway.