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Autosomal recessive variants in TUBGCP2 alter the gamma-tubulin ring complex leading to neurodevelopmental disease

2021    Gungor, Serdal; Oktay, Yavuz; Hiz, Semra; Aranguren-Ibanez, Alvaro; Kalafatcilar, Ipek; Yaramis, Ahmet; Karaca, Ezgi; Yis, Uluc; Sonmezler, Ece; Ekinci, Burcu; Aslan, Mahmut; Yilmaz, Elmasnur; Ozgor, Bilge; Balaraju, Sunitha; Szabo, Nora; Laurie, Steven; Beltran, Sergi; MacArthur, Daniel G.; Hathazi, Denisa; Topf, Ana; Topf, Ana

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (gamma-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish familywith dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in TUBGCP2 encoding the gamma-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 gamma-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 gamma-tubulin complex to the development of the central nervous system in humans.