Gehin, CharlotteLone, Museer ALee, WinstonCapolupo, LauraHo, SylviaAdeyemi, Adekemi MGerkes, Erica HStegmann, Alexander PaLopez-Martin, EstrellaBermejo-Sanchez, EvaMartinez-Delgado, BeatrizZweier, ChristianeKraus, CorneliaPopp, BerntStrehlow, VincentGräfe, DanielKnerr, InaJones, Eppie RZamuner, StefanoAbriata, Luciano AKunnathully, VidyaMoeller, Brandon EVocat, AnthonyRommelaere, SamuelBocquete, Jean-PhilippeRuchti, EvelyneLimoni, GretaVan Campenhoudt, MarineBourgeat, SamuelHenklein, PetraGilissen, Christianvan Bon, Bregje WPfundt, RolphWillemsen, Marjolein HSchieving, Jolanda HLeonardi, EmanuelaSoli, FiorenzaMurgia, AlessandraGuo, HuiZhang, QiumengXia, KunFagerberg, Christina RBeier, Christoph PLarsen, Martin JValenzuela, IreneFernández-Álvarez, PaulaXiong, ShiyiŚmigiel, RobertLópez-González, VanesaArmengol, LluísMorleo, ManuelaSelicorni, AngeloTorella, AnnalauraBlyth, MoiraCooper, Nicola SWilson, ValerieOegema, RenskeHerenger, YvanGarde, AuroreBruel, Ange-LineTran Mau-Them, FredericMaddocks, Alexis BrBain, Jennifer MBhat, Musadiq ACostain, GregoryKannu, PeterMarwaha, AshishChampaigne, Neena LFriez, Michael JRichardson, Ellen BGowda, Vykuntaraju KSrinivasan, Varunvenkat MGupta, YaskLim, Tze YSanna-Cherchi, SimoneLemaitre, BrunoYamaji, ToshiyukiHanada, KentaroBurke, John EJakšić, Ana MarjiaMcCabe, Brian DDe Los Rios, PaoloHornemann, ThorstenD'Angelo, GiovanniGennarino, Vincenzo A2023-06-062023-06-062023-05-15J Clin Invest. 2023 May 15;133(10):e165019.http://hdl.handle.net/20.500.12105/16150Neural 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.engVoRhttp://creativecommons.org/licenses/by/4.0/Cell BiologyGeneticsLipid raftsNeurodevelopmentCeramidesSphingolipidsHumansHomeostasisMutationAtribución 4.0 Internacional3697664813310e16501910.1172/JCI1650191558-8238The Journal of clinical investigationopen access