摘要：SummaryMicrotubules 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) inTUBGCP2encoding 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.Graphical AbstractDisplay OmittedHighlights•TUBGCP2variants cause neurodevelopmental delay, brain malformation, and epilepsy•The variant alters GCP2/GCP3 interaction and localization of GCP2 in cell cycle•We link GCP2 to the cytoskeleton, extracellular matrix, cell adhesion, and axon guidance•Functional proteomics is useful in establishing molecular pathways in rare diseasesBiological Sciences; Neuroscience; Molecular Neuroscience; Clinical Neuroscience; Systems Biology; Protemics
