van Kranenburg Melissa, Hoogeveen-Westerveld Marianne, Nellist Mark
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Hum Mutat. 2015 Feb;36(2):200-9. doi: 10.1002/humu.22723. Epub 2014 Nov 27.
The mechanistic target of rapamycin complex 1 (TORC1) senses nutrient availability to regulate eukaryotic anabolic metabolism. In response to limiting concentrations of amino acids, TORC1 kinase activity is inhibited through the GATOR-1 complex. Mutations in DEPDC5, that encodes one of the components of the GATOR-1 complex, have recently been associated with different forms of focal epilepsy. Here, we investigate the effects of 10 DEPDC5 variants identified in individuals with focal epilepsy and two DEPDC5 variants identified in serous ovarian tumors, on TORC1 signaling and GATOR-1 complex formation. According to our functional assessment, three variants clearly disrupted the DEPDC5-dependent inhibition of TORC1. We did not obtain functional evidence to support pathogenicity in the remaining cases. The observed functional differences between the DEPDC5 variants might underlie some of the clinical differences observed in the individuals carrying the different variants.
雷帕霉素复合物1（TORC1）的机制性靶点可感知营养物质的可用性，以调节真核生物的合成代谢。在氨基酸浓度受限的情况下，TORC1激酶活性通过GATOR-1复合物受到抑制。编码GATOR-1复合物成分之一的DEPDC5发生突变，最近已与不同形式的局灶性癫痫相关联。在此，我们研究了在局灶性癫痫患者中鉴定出的10种DEPDC5变体以及在浆液性卵巢肿瘤中鉴定出的两种DEPDC5变体对TORC1信号传导和GATOR-1复合物形成的影响。根据我们的功能评估，三种变体明显破坏了DEPDC5对TORC1的依赖性抑制作用。在其余病例中，我们未获得支持致病性的功能证据。观察到的DEPDC5变体之间的功能差异可能是携带不同变体的个体中观察到的一些临床差异的基础。
