Gehin, CharlotteCharlotteGehinLone, Museer AMuseer ALoneLee, WinstonWinstonLeeCapolupo, LauraLauraCapolupoHo, SylviaSylviaHoAdeyemi, Adekemi MAdekemi MAdeyemiGerkes, Erica HErica HGerkesStegmann, Alexander PaAlexander PaStegmannLópez-Martín, EstrellaEstrellaLópez-MartínBermejo-Sánchez, EvaEvaBermejo-SánchezMartínez-Delgado, BeatrizBeatrizMartínez-DelgadoZweier, Christiane GertrudChristiane GertrudZweierKraus, CorneliaCorneliaKrausPopp, BerntBerntPoppStrehlow, VincentVincentStrehlowGräfe, DanielDanielGräfeKnerr, InaInaKnerrJones, Eppie REppie RJonesZamuner, StefanoStefanoZamunerAbriata, Luciano ALuciano AAbriataKunnathully, VidyaVidyaKunnathullyMoeller, Brandon EBrandon EMoellerVocat, AnthonyAnthonyVocatRommelaere, SamuelSamuelRommelaereBocquete, Jean-PhilippeJean-PhilippeBocqueteRuchti, EvelyneEvelyneRuchtiLimoni, GretaGretaLimoniVan Campenhoudt, MarineMarineVan CampenhoudtBourgeat, SamuelSamuelBourgeatHenklein, PetraPetraHenkleinGilissen, ChristianChristianGilissenvan Bon, Bregje WBregje Wvan BonPfundt, RolphRolphPfundtWillemsen, Marjolein HMarjolein HWillemsenSchieving, Jolanda HJolanda HSchievingLeonardi, EmanuelaEmanuelaLeonardiSoli, FiorenzaFiorenzaSoliMurgia, AlessandraAlessandraMurgiaGuo, HuiHuiGuoZhang, QiumengQiumengZhangXia, KunKunXiaFagerberg, Christina RChristina RFagerbergBeier, Christoph PChristoph PBeierLarsen, Martin JMartin JLarsenValenzuela, IreneIreneValenzuelaFernández-Álvarez, PaulaPaulaFernández-ÁlvarezXiong, ShiyiShiyiXiongŚmigiel, RobertRobertŚmigielLópez-González, VanesaVanesaLópez-GonzálezArmengol, LluísLluísArmengolMorleo, ManuelaManuelaMorleoSelicorni, AngeloAngeloSelicorniTorella, AnnalauraAnnalauraTorellaBlyth, MoiraMoiraBlythCooper, Nicola SNicola SCooperWilson, ValerieValerieWilsonOegema, RenskeRenskeOegemaHerenger, YvanYvanHerengerGarde, AuroreAuroreGardeBruel, Ange-LineAnge-LineBruelTran Mau-Them, FredericFredericTran Mau-ThemMaddocks, Alexis BrAlexis BrMaddocksBain, Jennifer MJennifer MBainBhat, Musadiq AMusadiq ABhatCostain, GregoryGregoryCostainKannu, PeterPeterKannuMarwaha, AshishAshishMarwahaChampaigne, Neena LNeena LChampaigneFriez, Michael JMichael JFriezRichardson, Ellen BEllen BRichardsonGowda, Vykuntaraju KVykuntaraju KGowdaSrinivasan, Varunvenkat MVarunvenkat MSrinivasanGupta, YaskYaskGuptaLim, Tze YTze YLimSanna-Cherchi, SimoneSimoneSanna-CherchiLemaitre, BrunoBrunoLemaitreYamaji, ToshiyukiToshiyukiYamajiHanada, KentaroKentaroHanadaBurke, John EJohn EBurkeJakšić, Ana MarjiaAna MarjiaJakšićMcCabe, Brian DBrian DMcCabeDe Los Rios, PaoloPaoloDe Los RiosHornemann, ThorstenThorstenHornemannD'Angelo, GiovanniGiovanniD'AngeloGennarino, Vincenzo AVincenzo AGennarino2024-10-252024-10-252023-05-15https://boris-portal.unibe.ch/handle/20.500.12422/171883Neural 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.enCell Biology Genetics Lipid rafts Neurodevelopment600 - Technology::610 - Medicine & healtharticle10.48350/1896633697664810.1172/JCI165019