CERT1 mutations perturb human development by disrupting sphingolipid homeostasis
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, bu...
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-05-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI165019 |
| _version_ | 1827768175305949184 |
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| author | Charlotte Gehin Museer A. Lone Winston Lee Laura Capolupo Sylvia Ho Adekemi M. Adeyemi Erica H. Gerkes Alexander P.A. Stegmann Estrella López-Martín Eva Bermejo-Sánchez Beatriz Martínez-Delgado Christiane Zweier Cornelia Kraus Bernt Popp Vincent Strehlow Daniel Gräfe Ina Knerr Eppie R. Jones Stefano Zamuner Luciano A. Abriata Vidya Kunnathully Brandon E. Moeller Anthony Vocat Samuel Rommelaere Jean-Philippe Bocquete Evelyne Ruchti Greta Limoni Marine Van Campenhoudt Samuel Bourgeat Petra Henklein Christian Gilissen Bregje W. van Bon Rolph Pfundt Marjolein H. Willemsen Jolanda H. Schieving Emanuela Leonardi Fiorenza Soli Alessandra Murgia Hui Guo Qiumeng Zhang Kun Xia Christina R. Fagerberg Christoph P. Beier Martin J. Larsen Irene Valenzuela Paula Fernández-Álvarez Shiyi Xiong Robert Śmigiel Vanesa López-González Lluís Armengol Manuela Morleo Angelo Selicorni Annalaura Torella Moira Blyth Nicola S. Cooper Valerie Wilson Renske Oegema Yvan Herenger Aurore Garde Ange-Line Bruel Frederic Tran Mau-Them Alexis B.R. Maddocks Jennifer M. Bain Musadiq A. Bhat Gregory Costain Peter Kannu Ashish Marwaha Neena L. Champaigne Michael J. Friez Ellen B. Richardson Vykuntaraju K. Gowda Varunvenkat M. Srinivasan Yask Gupta Tze Y. Lim Simone Sanna-Cherchi Bruno Lemaitre Toshiyuki Yamaji Kentaro Hanada John E. Burke Ana Marjia Jakšić Brian D. McCabe Paolo De Los Rios Thorsten Hornemann Giovanni D’Angelo Vincenzo A. Gennarino |
| author_facet | Charlotte Gehin Museer A. Lone Winston Lee Laura Capolupo Sylvia Ho Adekemi M. Adeyemi Erica H. Gerkes Alexander P.A. Stegmann Estrella López-Martín Eva Bermejo-Sánchez Beatriz Martínez-Delgado Christiane Zweier Cornelia Kraus Bernt Popp Vincent Strehlow Daniel Gräfe Ina Knerr Eppie R. Jones Stefano Zamuner Luciano A. Abriata Vidya Kunnathully Brandon E. Moeller Anthony Vocat Samuel Rommelaere Jean-Philippe Bocquete Evelyne Ruchti Greta Limoni Marine Van Campenhoudt Samuel Bourgeat Petra Henklein Christian Gilissen Bregje W. van Bon Rolph Pfundt Marjolein H. Willemsen Jolanda H. Schieving Emanuela Leonardi Fiorenza Soli Alessandra Murgia Hui Guo Qiumeng Zhang Kun Xia Christina R. Fagerberg Christoph P. Beier Martin J. Larsen Irene Valenzuela Paula Fernández-Álvarez Shiyi Xiong Robert Śmigiel Vanesa López-González Lluís Armengol Manuela Morleo Angelo Selicorni Annalaura Torella Moira Blyth Nicola S. Cooper Valerie Wilson Renske Oegema Yvan Herenger Aurore Garde Ange-Line Bruel Frederic Tran Mau-Them Alexis B.R. Maddocks Jennifer M. Bain Musadiq A. Bhat Gregory Costain Peter Kannu Ashish Marwaha Neena L. Champaigne Michael J. Friez Ellen B. Richardson Vykuntaraju K. Gowda Varunvenkat M. Srinivasan Yask Gupta Tze Y. Lim Simone Sanna-Cherchi Bruno Lemaitre Toshiyuki Yamaji Kentaro Hanada John E. Burke Ana Marjia Jakšić Brian D. McCabe Paolo De Los Rios Thorsten Hornemann Giovanni D’Angelo Vincenzo A. Gennarino |
| author_sort | Charlotte Gehin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:08:40Z |
| format | Article |
| id | doaj.art-47a113198d5649e88315ddec99f2067f |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:08:40Z |
| publishDate | 2023-05-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-47a113198d5649e88315ddec99f2067f2023-11-07T16:20:20ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-05-0113310CERT1 mutations perturb human development by disrupting sphingolipid homeostasisCharlotte GehinMuseer A. LoneWinston LeeLaura CapolupoSylvia HoAdekemi M. AdeyemiErica H. GerkesAlexander P.A. StegmannEstrella López-MartínEva Bermejo-SánchezBeatriz Martínez-DelgadoChristiane ZweierCornelia KrausBernt PoppVincent StrehlowDaniel GräfeIna KnerrEppie R. JonesStefano ZamunerLuciano A. AbriataVidya KunnathullyBrandon E. MoellerAnthony VocatSamuel RommelaereJean-Philippe BocqueteEvelyne RuchtiGreta LimoniMarine Van CampenhoudtSamuel BourgeatPetra HenkleinChristian GilissenBregje W. van BonRolph PfundtMarjolein H. WillemsenJolanda H. SchievingEmanuela LeonardiFiorenza SoliAlessandra MurgiaHui GuoQiumeng ZhangKun XiaChristina R. FagerbergChristoph P. BeierMartin J. LarsenIrene ValenzuelaPaula Fernández-ÁlvarezShiyi XiongRobert ŚmigielVanesa López-GonzálezLluís ArmengolManuela MorleoAngelo SelicorniAnnalaura TorellaMoira BlythNicola S. CooperValerie WilsonRenske OegemaYvan HerengerAurore GardeAnge-Line BruelFrederic Tran Mau-ThemAlexis B.R. MaddocksJennifer M. BainMusadiq A. BhatGregory CostainPeter KannuAshish MarwahaNeena L. ChampaigneMichael J. FriezEllen B. RichardsonVykuntaraju K. GowdaVarunvenkat M. SrinivasanYask GuptaTze Y. LimSimone Sanna-CherchiBruno LemaitreToshiyuki YamajiKentaro HanadaJohn E. BurkeAna Marjia JakšićBrian D. McCabePaolo De Los RiosThorsten HornemannGiovanni D’AngeloVincenzo A. GennarinoNeural 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.https://doi.org/10.1172/JCI165019Cell biologyGenetics |
| spellingShingle | Charlotte Gehin Museer A. Lone Winston Lee Laura Capolupo Sylvia Ho Adekemi M. Adeyemi Erica H. Gerkes Alexander P.A. Stegmann Estrella López-Martín Eva Bermejo-Sánchez Beatriz Martínez-Delgado Christiane Zweier Cornelia Kraus Bernt Popp Vincent Strehlow Daniel Gräfe Ina Knerr Eppie R. Jones Stefano Zamuner Luciano A. Abriata Vidya Kunnathully Brandon E. Moeller Anthony Vocat Samuel Rommelaere Jean-Philippe Bocquete Evelyne Ruchti Greta Limoni Marine Van Campenhoudt Samuel Bourgeat Petra Henklein Christian Gilissen Bregje W. van Bon Rolph Pfundt Marjolein H. Willemsen Jolanda H. Schieving Emanuela Leonardi Fiorenza Soli Alessandra Murgia Hui Guo Qiumeng Zhang Kun Xia Christina R. Fagerberg Christoph P. Beier Martin J. Larsen Irene Valenzuela Paula Fernández-Álvarez Shiyi Xiong Robert Śmigiel Vanesa López-González Lluís Armengol Manuela Morleo Angelo Selicorni Annalaura Torella Moira Blyth Nicola S. Cooper Valerie Wilson Renske Oegema Yvan Herenger Aurore Garde Ange-Line Bruel Frederic Tran Mau-Them Alexis B.R. Maddocks Jennifer M. Bain Musadiq A. Bhat Gregory Costain Peter Kannu Ashish Marwaha Neena L. Champaigne Michael J. Friez Ellen B. Richardson Vykuntaraju K. Gowda Varunvenkat M. Srinivasan Yask Gupta Tze Y. Lim Simone Sanna-Cherchi Bruno Lemaitre Toshiyuki Yamaji Kentaro Hanada John E. Burke Ana Marjia Jakšić Brian D. McCabe Paolo De Los Rios Thorsten Hornemann Giovanni D’Angelo Vincenzo A. Gennarino CERT1 mutations perturb human development by disrupting sphingolipid homeostasis The Journal of Clinical Investigation Cell biology Genetics |
| title | CERT1 mutations perturb human development by disrupting sphingolipid homeostasis |
| title_full | CERT1 mutations perturb human development by disrupting sphingolipid homeostasis |
| title_fullStr | CERT1 mutations perturb human development by disrupting sphingolipid homeostasis |
| title_full_unstemmed | CERT1 mutations perturb human development by disrupting sphingolipid homeostasis |
| title_short | CERT1 mutations perturb human development by disrupting sphingolipid homeostasis |
| title_sort | cert1 mutations perturb human development by disrupting sphingolipid homeostasis |
| topic | Cell biology Genetics |
| url | https://doi.org/10.1172/JCI165019 |
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