Description: Lymphocyte functions triggered by antigen recognition and co-stimulation signals are associated with a rapid and intense cell division, and hence with metabolism adaptation. The nucleotide cytidine 5' triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids. CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthases (or synthetases) 1 and 2 (CTPS1 with CTPS2); the respective roles of these two enzymes are not known. CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes. Here we report the identification of a loss-of-function homozygous mutation (rs145092287) in CTPS1 in humans that causes a novel and life-threatening immunodeficiency, characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. In contrast, proximal and distal T-cell receptor (TCR) signalling events and responses were only weakly affected by the absence of CTPS1. Activated CTPS1-deficient cells had decreased levels of CTP. Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine. CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation. These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the immune response. CTPS1 may therefore represent a therapeutic target of immunosuppressive drugs that could specifically dampen lymphocyte activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martin, Emmanuel -- Palmic, Noe -- Sanquer, Sylvia -- Lenoir, Christelle -- Hauck, Fabian -- Mongellaz, Cedric -- Fabrega, Sylvie -- Nitschke, Patrick -- Esposti, Mauro Degli -- Schwartzentruber, Jeremy -- Taylor, Naomi -- Majewski, Jacek -- Jabado, Nada -- Wynn, Robert F -- Picard, Capucine -- Fischer, Alain -- Arkwright, Peter D -- Latour, Sylvain -- G1001799/Medical Research Council/United Kingdom -- WT095219MA/Wellcome Trust/United Kingdom -- England -- Nature. 2014 Jun 12;510(7504):288-92. doi: 10.1038/nature13386. Epub 2014 May 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratoire Activation Lymphocytaire et Susceptibilite a l'EBV, INSERM UMR 1163, Hopital Necker Enfants-Malades, Paris 75015, France [2] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France. ; Laboratoire de Biochimie Metabolomique et Proteomique, Hopital Necker Enfants-Malades, Paris 75015, France. ; Hematopoiesis and Immunotherapy, CNRS-UMR 5535, Institut de Genetique Moleculaire de Montpellier, Montpellier 34293, France. ; 1] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France [2] Plateforme Vecteurs Viraux et Transfert de Genes, IFR94, Hopital Necker Enfants-Malades, Paris 75015, France. ; 1] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France [2] Service de Bioinformatique, Hopital Necker Enfants-Malades, Paris 75015, France. ; 1] University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK [2] Italian Institute of Technology, Genoa 16163, Italy. ; McGill University and Genome Quebec Innovation Centre, Montreal H3A 0G1, Canada. ; 1] McGill University and Genome Quebec Innovation Centre, Montreal H3A 0G1, Canada [2] Department of Pediatrics, McGill University Health Center Research Institute, Montreal H3H 1P3, Canada. ; University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK. ; 1] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France [2] Centre d'Etude des Deficits Immunitaires, Hopital Necker Enfants-Malades, AP-HP, Paris 75015, France [3] Laboratoire Genetique Humaine des Maladies Infectieuses, INSERM UMR 1163, Hopital Necker Enfants-Malades, Paris 75015, France. ; 1] Laboratoire Activation Lymphocytaire et Susceptibilite a l'EBV, INSERM UMR 1163, Hopital Necker Enfants-Malades, Paris 75015, France [2] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France [3] Unite d'Immunologie et Hematologie Pediatrique, Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Necker Enfants-Malades, Paris 75015, France [4] College de France, Paris 75005, France. ; 1] University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK [2]. ; 1] Laboratoire Activation Lymphocytaire et Susceptibilite a l'EBV, INSERM UMR 1163, Hopital Necker Enfants-Malades, Paris 75015, France [2] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France [3] Laboratoire de Biochimie Metabolomique et Proteomique, Hopital Necker Enfants-Malades, Paris 75015, France [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870241" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138491/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138491/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉H3Africa Consortium -- Rotimi, Charles -- Abayomi, Akin -- Abimiku, Alash'le -- Adabayeri, Victoria May -- Adebamowo, Clement -- Adebiyi, Ezekiel -- Ademola, Adebowale D -- Adeyemo, Adebowale -- Adu, Dwomoa -- Affolabi, Dissou -- Agongo, Godfred -- Ajayi, Samuel -- Akarolo-Anthony, Sally -- Akinyemi, Rufus -- Akpalu, Albert -- Alberts, Marianne -- Alonso Betancourt, Orlando -- Alzohairy, Ahmed Mansour -- Ameni, Gobena -- Amodu, Olukemi -- Anabwani, Gabriel -- Andersen, Kristian -- Arogundade, Fatiu -- Arulogun, Oyedunni -- Asogun, Danny -- Bakare, Rasheed -- Balde, Naby -- Baniecki, Mary Lynn -- Beiswanger, Christine -- Benkahla, Alia -- Bethke, Lara -- Boehnke, Micheal -- Boima, Vincent -- Brandful, James -- Brooks, Andrew I -- Brosius, Frank C -- Brown, Chester -- Bucheton, Bruno -- Burke, David T -- Burnett, Barrington G -- Carrington-Lawrence, Stacy -- Carstens, Nadia -- Chisi, John -- Christoffels, Alan -- Cooper, Richard -- Cordell, Heather -- Crowther, Nigel -- Croxton, Talishiea -- de Vries, Jantina -- Derr, Leslie -- Donkor, Peter -- Doumbia, Seydou -- Duncanson, Audrey -- Ekem, Ivy -- El Sayed, Ahmed -- Engel, Mark E -- Enyaru, John C K -- Everett, Dean -- Fadlelmola, Faisal M -- Fakunle, Eyitayo -- Fischbeck, Kenneth H -- Fischer, Anne -- Folarin, Onikepe -- Gamieldien, Junaid -- Garry, Robert F -- Gaseitsiwe, Simani -- Gbadegesin, Rasheed -- Ghansah, Anita -- Giovanni, Maria -- Goesbeck, Parham -- Gomez-Olive, F Xavier -- Grant, Donald S -- Grewal, Ravnit -- Guyer, Mark -- Hanchard, Neil A -- Happi, Christian T -- Hazelhurst, Scott -- Hennig, Branwen J -- Hertz-, Christiane -- Fowler -- Hide, Winston -- Hilderbrandt, Friedhelm -- Hugo-Hamman, Christopher -- Ibrahim, Muntaser E -- James, Regina -- Jaufeerally-Fakim, Yasmina -- Jenkins, Carolyn -- Jentsch, Ute -- Jiang, Pan-Pan -- Joloba, Moses -- Jongeneel, Victor -- Joubert, Fourie -- Kader, Mukthar -- Kahn, Kathleen -- Kaleebu, Pontiano -- Kapiga, Saidi H -- Kassim, Samar Kamal -- Kasvosve, Ishmael -- Kayondo, Jonathan -- Keavney, Bernard -- Kekitiinwa, Adeodata -- Khan, Sheik Humarr -- Kimmel, Paul -- King, Mary-Claire -- Kleta, Robert -- Koffi, Mathurin -- Kopp, Jeffrey -- Kretzler, Matthias -- Kumuthini, Judit -- Kyobe, Samuel -- Kyobutungi, Catherine -- Lackland, Daniel T -- Lacourciere, Karen A -- Landoure, Guida -- Lawlor, Rita -- Lehner, Thomas -- Lesosky, Maia -- Levitt, Naomi -- Littler, Katherine -- Lombard, Zane -- Loring, Jeanne F -- Lyantagaye, Sylvester -- Macleod, Annette -- Madden, Ebony B -- Mahomva, Chengetai R -- Makani, Julie -- Mamven, Manmak -- Marape, Marape -- Mardon, Graeme -- Marshall, Patricia -- Martin, Darren P -- Masiga, Daniel -- Mason, Robin -- Mate-Kole, Michael -- Matovu, Enock -- Mayige, Mary -- Mayosi, Bongani M -- Mbanya, Jean Claude -- McCurdy, Sheryl A -- McCarthy, Mark I -- McIlleron, Helen -- Mc'Ligeyo, S O -- Merle, Corrine -- Mocumbi, Ana Olga -- Mondo, Charles -- Moran, John V -- Motala, Ayesha -- Moxey-Mims, Marva -- Mpoloka, Wata Sununguko -- Msefula, Chisomo L -- Mthiyane, Thuli -- Mulder, Nicola -- Mulugeta, Gebregziab her -- Mumba, Dieuodonne -- Musuku, John -- Nagdee, Mo -- Nash, Oyekanmi -- Ndiaye, Daouda -- Nguyen, Anh Quynh -- Nicol, Mark -- Nkomazana, Oathokwa -- Norris, Shane -- Nsangi, Betty -- Nyarko, Alexander -- Nyirenda, Moffat -- Obe, Eileen -- Obiakor, Reginald -- Oduro, Abraham -- Ofori-Acquah, Solomon F -- Ogah, Okechukwu -- Ogendo, Stephen -- Ohene-Frempong, Kwaku -- Ojo, Akinlolu -- Olanrewaju, Timothy -- Oli, John -- Osafo, Charlotte -- Ouwe Missi Oukem-Boyer, Odile -- Ovbiagele, Bruce -- Owen, Andrew -- Owolabi, Mayowa Ojo -- Owolabi, Lukman -- Owusu-Dabo, Ellis -- Pare, Guillaume -- Parekh, Rulan -- Patterton, Hugh G -- Penno, Margaret B -- Peterson, Jane -- Pieper, Rembert -- Plange-Rhule, Jacob -- Pollak, Martin -- Puzak, Julia -- Ramesar, Rajkumar S -- Ramsay, Michele -- Rasooly, Rebekah -- Reddy, Shiksha -- Sabeti, Pardis C -- Sagoe, Kwamena -- Salako, Tunde -- Samassekou, Oumar -- Sandhu, Manjinder S -- Sankoh, Osman -- Sarfo, Fred Stephen -- Sarr, Marie -- Shaboodien, Gasnat -- Sidibe, Issa -- Simo, Gustave -- Simuunza, Martin -- Smeeth, Liam -- Sobngwi, Eugene -- Soodyall, Himla -- Sorgho, Hermann -- Sow Bah, Oumou -- Srinivasan, Sudha -- Stein, Dan J -- Susser, Ezra S -- Swanepoel, Carmen -- Tangwa, Godfred -- Tareila, Andrew -- Tastan Bishop, Ozlem -- Tayo, Bamidele -- Tiffin, Nicki -- Tinto, Halidou -- Tobin, Ekaete -- Tollman, Stephen Meir -- Traore, Mahamadou -- Treadwell, Marsha J -- Troyer, Jennifer -- Tsimako-Johnstone, Masego -- Tukei, Vincent -- Ulasi, Ifeoma -- Ulenga, Nzovu -- van Rooyen, Beverley -- Wachinou, Ablo Prudence -- Waddy, Salina P -- Wade, Alisha -- Wayengera, Misaki -- Whitworth, James -- Wideroff, Louise -- Winkler, Cheryl A -- Winnicki, Sarah -- Wonkam, Ambroise -- Yewondwos, Mengistu -- sen, Tadase -- Yozwiak, Nathan -- Zar, Heather -- 085349/Wellcome Trust/United Kingdom -- 095009/Wellcome Trust/United Kingdom -- 095201/Wellcome Trust/United Kingdom -- 098504/Wellcome Trust/United Kingdom -- 104111/Wellcome Trust/United Kingdom -- MC_U123292700/Medical Research Council/United Kingdom -- P20 MD006899/MD/NIMHD NIH HHS/ -- R01 AI104621/AI/NIAID NIH HHS/ -- RG/08/012/25941/British Heart Foundation/United Kingdom -- U01 HG007044/HG/NHGRI NIH HHS/ -- U41 HG006941/HG/NHGRI NIH HHS/ -- U54 AI110398/AI/NIAID NIH HHS/ -- U54 HG006938/HG/NHGRI NIH HHS/ -- U54 HG006939/HG/NHGRI NIH HHS/ -- U54 HG007479/HG/NHGRI NIH HHS/ -- UH2 HG007051/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 20;344(6190):1346-8. doi: 10.1126/science.1251546.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24948725" target="_blank"〉PubMed〈/a〉