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oai:repisalud.isciii.es:20.500.12105/161502025-05-30T11:44:12Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616

00925njm 22002777a 4500 dc Gehin, Charlotte author Lone, Museer A author Lee, Winston author Capolupo, Laura author Ho, Sylvia author Adeyemi, Adekemi M author Gerkes, Erica H author Stegmann, Alexander Pa author Lopez-Martin, Estrella author Bermejo-Sanchez, Eva author Martinez-Delgado, Beatriz author Zweier, Christiane author Kraus, Cornelia author Popp, Bernt author Strehlow, Vincent author Gräfe, Daniel author Knerr, Ina author Jones, Eppie R author Zamuner, Stefano author Abriata, Luciano A author Kunnathully, Vidya author Moeller, Brandon E author Vocat, Anthony author Rommelaere, Samuel author Bocquete, Jean-Philippe author Ruchti, Evelyne author Limoni, Greta author Van Campenhoudt, Marine author Bourgeat, Samuel author Henklein, Petra author Gilissen, Christian author van Bon, Bregje W author Pfundt, Rolph author Willemsen, Marjolein H author Schieving, Jolanda H author Leonardi, Emanuela author Soli, Fiorenza author Murgia, Alessandra author Guo, Hui author Zhang, Qiumeng author Xia, Kun author Fagerberg, Christina R author Beier, Christoph P author Larsen, Martin J author Valenzuela, Irene author Fernández-Álvarez, Paula author Xiong, Shiyi author Śmigiel, Robert author López-González, Vanesa author Armengol, Lluís author Morleo, Manuela author Selicorni, Angelo author Torella, Annalaura author Blyth, Moira author Cooper, Nicola S author Wilson, Valerie author Oegema, Renske author Herenger, Yvan author Garde, Aurore author Bruel, Ange-Line author Tran Mau-Them, Frederic author Maddocks, Alexis Br author Bain, Jennifer M author Bhat, Musadiq A author Costain, Gregory author Kannu, Peter author Marwaha, Ashish author Champaigne, Neena L author Friez, Michael J author Richardson, Ellen B author Gowda, Vykuntaraju K author Srinivasan, Varunvenkat M author Gupta, Yask author Lim, Tze Y author Sanna-Cherchi, Simone author Lemaitre, Bruno author Yamaji, Toshiyuki author Hanada, Kentaro author Burke, John E author Jakšić, Ana Marjia author McCabe, Brian D author De Los Rios, Paolo author Hornemann, Thorsten author D'Angelo, Giovanni author Gennarino, Vincenzo A author 2023-05-15 Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome. J Clin Invest. 2023 May 15;133(10):e165019. 10.1172/JCI165019 1558-8238 The Journal of clinical investigation 36976648 http://hdl.handle.net/20.500.12105/16150 Cell Biology Genetics Lipid rafts Neurodevelopment CERT1 mutations perturb human development by disrupting sphingolipid homeostasis