Identification of mutations in CUL7 in 3-M syndrome
Identification of mutations in CUL7 in 3-M syndrome
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DOI：
10.1038/ng1628
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发表时间：
2005-10-01
期刊：
影响因子：
30.8
通讯作者：
Cormier-Daire, V
中科院分区：
文献类型：
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作者：
Huber, C;Dias-Santagata, D;Cormier-Daire, V
宫内生长迟缓是由母体、胎儿或胎盘因素引起的，导致血管内滋养细胞侵袭受损和胎盘灌注减少(1)。虽然各种原因的宫内生长迟缓已确定，大多数情况下仍无法解释。3-M综合征（OMIM 273750）是一种常染色体隐性遗传病，以严重的产前和产后生长迟缓为特征，研究了29个3-M综合征（OMIM 273750）家族，我们首先将其定位在染色体6p21.1上，然后确定了基因cullin 7 （CUL7）的25个不同突变。CUL7组装含有Skp1、Fbx29（也称为Fbw8）和ROC1的E3泛素连接酶复合物，并促进泛素化。通过缺失分析，我们发现CUL7利用其中心区域与Skp1-Fbx29异源二聚体相互作用。功能研究表明，3- m相关的CUL7无义突变R1445X和错义突变H1464P分别导致CUL7缺乏募集ROC1。这些结果提示泛素化受损可能在人类宫内生长迟缓的发病机制中起作用。
Intrauterine growth retardation is caused by maternal, fetal or placental factors that result in impaired endovascular trophoblast invasion and reduced placental perfusion(1). Although various causes of intrauterine growth retardation have been identified, most cases remain unexplained. Studying 29 families with 3-M syndrome (OMIM 273750), an autosomal recessive condition characterized by severe pre- and postnatal growth retardation, we first mapped the underlying gene to chromosome 6p21.1 and then identified 25 distinct mutations in the gene cullin 7 (CUL7). CUL7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8) and ROC1 and promotes ubiquitination. Using deletion analysis, we found that CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer. Functional studies indicated that the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1. These results suggest that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans.