iScience (Jan 2021)
Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease
- Serdal Gungor,
- Yavuz Oktay,
- Semra Hiz,
- Álvaro Aranguren-Ibáñez,
- Ipek Kalafatcilar,
- Ahmet Yaramis,
- Ezgi Karaca,
- Uluc Yis,
- Ece Sonmezler,
- Burcu Ekinci,
- Mahmut Aslan,
- Elmasnur Yilmaz,
- Bilge Özgör,
- Sunitha Balaraju,
- Nora Szabo,
- Steven Laurie,
- Sergi Beltran,
- Daniel G. MacArthur,
- Denisa Hathazi,
- Ana Töpf,
- Andreas Roos,
- Hanns Lochmuller,
- Isabelle Vernos,
- Rita Horvath
Affiliations
- Serdal Gungor
- Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Paediatric Neurology, Malatya, Turkey
- Yavuz Oktay
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey; Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University and Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
- Semra Hiz
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey; Dokuz Eylul University, Faculty of Medicine, Department of Pediatric Neurology Izmir, Turkey
- Álvaro Aranguren-Ibáñez
- Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain
- Ipek Kalafatcilar
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey; Dokuz Eylul University, Faculty of Medicine, Department of Pediatric Neurology Izmir, Turkey
- Ahmet Yaramis
- Pediatric Neurology Clinic, Private Office, Diyarbakir, Turkey
- Ezgi Karaca
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey; Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University and Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
- Uluc Yis
- Dokuz Eylul University, Faculty of Medicine, Department of Pediatric Neurology Izmir, Turkey
- Ece Sonmezler
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey
- Burcu Ekinci
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey
- Mahmut Aslan
- Dokuz Eylul University, Faculty of Medicine, Department of Pediatric Neurology Izmir, Turkey
- Elmasnur Yilmaz
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey
- Bilge Özgör
- Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Paediatric Neurology, Malatya, Turkey
- Sunitha Balaraju
- John Walton Muscular Dystrophy Research Centre, Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK; Department of Clinical Neurosciences, John Van Geest Cambridge Centre for Brain Repair, University of Cambridge School of Clinical Medicine, Robinson Way, Cambridge CB2 0PY, UK
- Nora Szabo
- Department of Clinical Neurosciences, John Van Geest Cambridge Centre for Brain Repair, University of Cambridge School of Clinical Medicine, Robinson Way, Cambridge CB2 0PY, UK; Budai Children Hospital, Észak-Közép-budai Centrum, Új Szent János Kórház és Szakrendelő, Budapest, Hungary
- Steven Laurie
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
- Sergi Beltran
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
- Daniel G. MacArthur
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Denisa Hathazi
- Department of Clinical Neurosciences, John Van Geest Cambridge Centre for Brain Repair, University of Cambridge School of Clinical Medicine, Robinson Way, Cambridge CB2 0PY, UK
- Ana Töpf
- John Walton Muscular Dystrophy Research Centre, Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK
- Andreas Roos
- Leibniz Institut für Analytische Wissenschaften, ISAS, Dortmund, Germany & Pediatric Neurology, University Hospital, University of Duisburg-Essen, Faculty of Medicine, Essen, Germany
- Hanns Lochmuller
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain; Children's Hospital of Eastern Ontario Research Institute; Division of Neurology, Department of Medicine, the Ottawa Hospital; and Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada
- Isabelle Vernos
- Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Spain
- Rita Horvath
- Department of Clinical Neurosciences, John Van Geest Cambridge Centre for Brain Repair, University of Cambridge School of Clinical Medicine, Robinson Way, Cambridge CB2 0PY, UK; Corresponding author
- Journal volume & issue
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Vol. 24,
no. 1
p. 101948
Abstract
Summary: 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.
