Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in TUBGCP2 encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans.

微管有助于构建神经元和其他细胞的细胞骨架。先前已报道了人类神经发育疾病中γ-微管蛋白（γ-微管蛋白）复合物的几种成分。我们描述了来自土耳其近亲家庭的两个兄弟姐妹，他们患有畸形特征、发育迟缓、脑畸形和癫痫，在编码 γ-微管蛋白复合物 2 (GCP2) 蛋白的TUBGCP2中携带纯合突变 (p.Glu311Lys)。预计该变体会破坏 GCP2 与 GCP3 的静电相互作用。在携带该变体的原代成纤维细胞中，我们观察到细胞周期期间 γ-微管蛋白微弱离域，但 GCP2 蛋白水平正常。通过质谱分析，我们观察到多种蛋白质的失调，这些蛋白质参与细胞骨架和细胞外基质的组装和组织，控制细胞粘附，以及对神经元稳态（包括轴突引导）至关重要的蛋白质。总之，我们的功能和蛋白质组学研究将 TUBGCP2 和 γ-微管蛋白复合物与人类中枢神经系统的发育联系起来。