1. Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation
- Author
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Tracy A Briggs, Emmanuel Martin, Sylvia Sanquer, Alain Fischer, Capucine Picard, Norbert Minet, Claire Soudais, Maria Leites-de-Moraes, Smita Y. Patel, Anne-Claire Boschat, Robert Wynn, Jean-Pierre de Villartay, Stephen M. Hughes, Tim Bourne, Sylvain Latour, Steicy Sobrino, Sophie Hambleton, Peter D. Arkwright, Monica G. Lawrence, Christelle Lenoir, Centre d'études spatiales de la biosphère (CESBIO), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Institut des Vaisseaux et du Sang, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie métabolique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Centre d'étude des Déficits Immunitaires, Génétique Humaine des Maladies Infectieuses (Inserm U980), Newcastle University [Newcastle], Nuffield Department of Surgery, University of Oxford [Oxford], Royal Manchester Children's Hospital, University of Manchester [Manchester], Dept Clin Biochem & Immunol, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Leite de Moraes, Maria do Carmo, University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris, University of Oxford, Magellium, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Chaire Médecine expérimentale (A. Fischer), and Collège de France (CdF (institution))
- Subjects
0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Lymphocyte ,T cell ,T-cell leukemia ,Lymphocytes/immunology ,Lymphocyte Activation ,Cell Line ,Immunophenotyping ,Frameshift mutation ,Jurkat Cells ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Humans ,Carbon-Nitrogen Ligases ,Lymphocytes ,ComputingMilieux_MISCELLANEOUS ,Cell Proliferation ,Chemistry ,Cell growth ,Homozygote ,Cell Differentiation ,General Medicine ,Natural killer T cell ,Acquired immune system ,Molecular biology ,3. Good health ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,medicine.anatomical_structure ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,030220 oncology & carcinogenesis ,Mutation ,Carbon-Nitrogen Ligases/genetics ,CRISPR-Cas Systems ,Research Article - Abstract
International audience; Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1 T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1 T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1 T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1 T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.
- Published
- 2020