Defective tubulin detyrosination causes structural brain abnormalities with cognitive deficiency in humans and mice
Autor: | Pagnamenta, AT, Heemeryck, P, Martin, HC, Bosc, C, Peris, L, Uszynski, I, Gory-Fauré, S, Couly, S, Deshpande, C, Siddiqui, A, Elmonairy, AA, Consortium, WGS500, Consortium, Genomics England Research, Jayawant, S, Murthy, S, Walker, I, Loong, L, Bauer, P, Vossier, F, Denarier, E, Maurice, T, Barbier, EL, Deloulme, J-C, Taylor, JC, Blair, EM, Andrieux, A, Moutin, M-J |
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Přispěvatelé: | Oxford NIHR Biomedical Research Centre, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), The Wellcome Trust Sanger Institute [Cambridge], Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Guy's Hospital [London], Kings College Hospital, Ministry of Health [Koweït], John Radcliffe Hospital [Oxford University Hospital], Upton Hospital [Slough, Royaume-uni], Wexham Park Hospital [Slough, Royaume-Uni], Oxford University Hospitals NHS Trust, University of Oxford [Oxford], CENTOGENE AG, Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Oxford |
Rok vydání: | 2019 |
Předmět: | |
Zdroj: | Hum Mol Genet Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2019, ⟨10.1093/hmg/ddz186⟩ Human Molecular Genetics, 2019, ⟨10.1093/hmg/ddz186⟩ |
ISSN: | 1460-2083 0964-6906 |
DOI: | 10.1093/hmg/ddz186⟩ |
Popis: | Reversible detyrosination of tubulin, the building block of microtubules, is crucial for neuronal physiology. Enzymes responsible for detyrosination were recently identified as complexes of vasohibins (VASHs) one or two with small VASH-binding protein (SVBP). Here we report three consanguineous families, each containing multiple individuals with biallelic inactivation of SVBP caused by truncating variants (p.Q28(*) and p.K13Nfs(*)18). Affected individuals show brain abnormalities with microcephaly, intellectual disability and delayed gross motor and speech development. Immunoblot testing in cells with pathogenic SVBP variants demonstrated that the encoded proteins were unstable and non-functional, resulting in a complete loss of VASH detyrosination activity. Svbp knockout mice exhibit drastic accumulation of tyrosinated tubulin and a reduction of detyrosinated tubulin in brain tissue. Similar alterations in tubulin tyrosination levels were observed in cultured neurons and associated with defects in axonal differentiation and architecture. Morphological analysis of the Svbp knockout mouse brains by anatomical magnetic resonance imaging showed a broad impact of SVBP loss, with a 7% brain volume decrease, numerous structural defects and a 30% reduction of some white matter tracts. Svbp knockout mice display behavioural defects, including mild hyperactivity, lower anxiety and impaired social behaviour. They do not, however, show prominent memory defects. Thus, SVBP-deficient mice recapitulate several features observed in human patients. Altogether, our data demonstrate that deleterious variants in SVBP cause this neurodevelopmental pathology, by leading to a major change in brain tubulin tyrosination and alteration of microtubule dynamics and neuron physiology. |
Databáze: | OpenAIRE |
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