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

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dc.authoridKaraca, Ezgi/0000-0002-4926-7991
dc.authoridBeltran, Sergi/0000-0002-2810-3445
dc.authoridMacArthur, Daniel/0000-0002-5771-2290
dc.authoridYilmaz, Elmasnur/0000-0001-9711-0203
dc.authoridAranguren-Ibanez, Alvaro/0000-0001-8929-3521
dc.authoridOktay, Yavuz/0000-0002-0158-2693
dc.authorwosidKALAFATCILAR POLAT, Ayşe İpek/A-9714-2016
dc.authorwosidKaraca, Ezgi/P-1759-2019
dc.authorwosidBeltran, Sergi/I-3408-2015
dc.authorwosidVernos, Isabelle/C-1687-2015
dc.authorwosidOktay, Yavuz/G-4794-2015
dc.contributor.authorGungor, Serdal
dc.contributor.authorOktay, Yavuz
dc.contributor.authorHiz, Semra
dc.contributor.authorAranguren-Ibanez, Alvaro
dc.contributor.authorKalafatcilar, Ipek
dc.contributor.authorYaramis, Ahmet
dc.contributor.authorKaraca, Ezgi
dc.date.accessioned2024-08-04T20:49:10Z
dc.date.available2024-08-04T20:49:10Z
dc.date.issued2021
dc.departmentİnönü Üniversitesien_US
dc.description.abstractMicrotubules 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.en_US
dc.description.sponsorshipTurkish Scientific and Research Council (TUBITAK) [216S771]; Turkish Academy of Sciences Young Investigator Programme (TUBA-GEBIP); Wellcome Centre for Mitochondrial Research [109915/Z/15/Z, 203105/Z/16/Z]; Medical Research Council (UK) [MR/N025431/1]; European Research Council [309548]; Wellcome Trust Pathfinder Scheme [201064/Z/16/Z]; Newton Fund (UK/Turkey) [MR/N027302/1]; Evelyn Trust; Lily Foundation; MRC [MR/S005021/1]; French Muscular Dystrophy Association (AFM-Telethon) [21466]; National Human Genome Research Institute [UM1 HG008900, R01 HG009141]; National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program; National Eye Institute; AGAUR [2017 SGR 478]; Spanish ministry of science, innovation and universities [PGC2018-096976-B-I00]; Canadian Institutes of Health Research [FDN-167281]; Muscular Dystrophy Canada; Canada Foundation for Innovation [CFI-JELF 38412]; Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health) [950-232279]; RD-Connect Genome-Phenome Analysis Platform [305444]; European Joint Programme in Rare Disease (EJP-RD); INB/ELIXIR-ES; Canadian Institutes of Health Research; MRC [G1000848, MR/N010035/1, MR/N025431/2, MR/N025431/1] Funding Source: UKRIen_US
dc.description.sponsorshipThis study was supported by the Turkish Scientific and Research Council (TUBITAK) research grant 216S771. Y.O. is supported by Turkish Academy of Sciences Young Investigator Programme (TUBA-GEBIP). R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), Medical Research Council (UK) (MR/N025431/1), the European Research Council (309548), the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z), the Newton Fund (UK/Turkey, MR/N027302/1), Evelyn Trust, Lily Foundation, and MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD, MR/S005021/1). A.R. received financial support by the French Muscular Dystrophy Association (AFM-Telethon; grant 21466). TheMinisteriumfur Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Senatsverwaltung fur Wirtschaft, Technologie und Forschung des Landes Berlin and the Bundesministerium fur Bildung und Forschung is gratefully acknowledged. Sequence analysis was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics and was funded by the National Human Genome Research Institute (UM1 HG008900 and R01 HG009141) with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. I.V. and A.A.I. were supported by the CRG internal funds, grant 2017 SGR 478 from AGAUR and grant PGC2018-096976-B-I00 from the Spanish ministry of science, innovation and universities. H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). Data were analyzed using the RD-Connect Genome-Phenome Analysis Platform developed under FP7/2007-2013 funded project (grant agreement no 305444) and funding from European Joint Programme in Rare Disease (EJP-RD) and INB/ELIXIR-ES.en_US
dc.identifier.doi10.1016/j.isci.2020.101948
dc.identifier.issn2589-0042
dc.identifier.issue1en_US
dc.identifier.pmid33458610en_US
dc.identifier.scopus2-s2.0-85098594269en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1016/j.isci.2020.101948
dc.identifier.urihttps://hdl.handle.net/11616/99692
dc.identifier.volume24en_US
dc.identifier.wosWOS:000612996900067en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.ispartofIscienceen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectL-Serineen_US
dc.subjectMicrotubule Nucleationen_US
dc.subjectBrainen_US
dc.subjectDeficiencyen_US
dc.subjectMutationsen_US
dc.subjectPromotesen_US
dc.titleAutosomal recessive variants in TUBGCP2 alter the ?-tubulin ring complex leading to neurodevelopmental diseaseen_US
dc.typeArticleen_US

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