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.

运输所需的内体分选复合物 (ESCRT) 对于多膜建模和膜独立细胞过程至关重要。在这里，我们描述了六个不相关的人从头影响 VPS4A ATPase 结构域的错义变体，VPS4A 是一种调节 ESCRT 功能的关键酶。先证者有脑结构异常、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 突变体的过度表达导致增大的内体液泡，类似于由已知显性负性 ATP 酶缺陷形式的 VPS4A 的表达诱导的液泡。先证者来源的成纤维细胞具有扩大的内体结构，并在限制膜上异常积累 ESCRT 蛋白 IST1。在 iPSC 衍生的人类神经元中，正常内体形态和 IST1 定位也需要 VPS4A 功能。突变影响了其他 ESCRT 依赖的细胞过程，包括中心体数量的调节、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。因此，我们表征了由影响VPS4A并证明其正常功能是多种人类发育和细胞过程所必需的。