Watts Giles D J, Wymer Jill, Kovach Margaret J, Mehta Sarju G, Mumm Steven, Darvish Daniel, Pestronk Alan, Whyte Michael P, Kimonis Virginia E
Division of Genetics, Children's Hospital Boston, 300 Longwood Avenue, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nat Genet. 2004 Apr;36(4):377-81. doi: 10.1038/ng1332. Epub 2004 Mar 21.
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 approximately 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.
伴有骨Paget病和额颞叶痴呆的包涵体肌病（IBMPFD）是一种显性进行性疾病，定位于9号染色体p21.1 - p12区域。我们采用候选基因方法对13个与9号染色体连锁的IBMPFD家系进行了研究。我们在所有61名受累个体中仅发现了编码含缬酪肽蛋白（VCP，AAA - ATP酶超家族成员）的基因中的六个错义突变。单倍型分析表明，两个北美家系中两个奠基者的后代约占50%受累家系的IBMPFD病例。VCP与多种细胞活动相关，包括细胞周期调控、膜融合和泛素 - 蛋白酶体降解途径。将VCP鉴定为导致IBMPFD的病因对其他包涵体疾病具有重要意义，包括肌病、痴呆和骨Paget病（PDB），因为它可能定义了一种新的基于泛素的常见病理途径。
