Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
Am J Hum Genet. 2020 Dec 3;107(6):1129-1148. doi: 10.1016/j.ajhg.2020.10.012. Epub 2020 Nov 12.
The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.
内体分选复合物需要运输 (ESCRTs) 对于多种膜建模和膜独立的细胞过程都是必不可少的。在这里，我们描述了六个无关个体的从头错义变异，这些变异影响 VPS4A 的 ATP 酶结构域，VPS4A 是调节 ESCRT 功能的关键酶。先证者具有结构脑异常、严重的神经发育迟缓、白内障、生长障碍和贫血。在培养的细胞中，VPS4A 突变体的过表达导致内体空泡增大，类似于表达已知的显性失活 ATP 酶缺陷形式的 VPS4A 诱导的内体空泡。源自先证者的成纤维细胞具有增大的内体结构，ESCRT 蛋白 IST1 在限制膜上异常积累。VPS4A 功能对于人诱导多能干细胞源性神经元中的正常内体形态和 IST1 定位也是必需的。突变影响其他 ESCRT 依赖性细胞过程，包括中心体数量、初级纤毛形态、核膜形态、染色体分离、有丝分裂纺锤体形成和细胞周期进程的调节。因此，我们描述了一种由影响 VPS4A 的突变引起的独特的多系统疾病，并证明其正常功能对于多种人类发育和细胞过程都是必需的。
