CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Charlotte Gehin; Museer A Lone; Winston Lee; Laura Capolupo; Sylvia Ho; Adekemi M Adeyemi; Erica H Gerkes; Alexander Pa 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 Br 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 Marija Jakšić; Brian D McCabe; Paolo De Los Rios; Thorsten Hornemann; Giovanni D'Angelo; Vincenzo A Gennarino

doi:10.1172/JCI165019

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Charlotte Gehin, Museer A Lone, Winston Lee, Laura Capolupo, Sylvia Ho, Adekemi M Adeyemi, Erica H Gerkes, Alexander Pa 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 AbriataVidya 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 Br 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 Marija Jakšić, Brian D McCabe, Paolo De Los Rios, Thorsten Hornemann, Giovanni D'Angelo, Vincenzo A Gennarino

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Abstract

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.

Original language	English
Article number	e165019
Journal	Journal of Clinical Investigation
Volume	133
Issue number	10
Early online date	28 Mar 2023
DOIs	https://doi.org/10.1172/JCI165019
Publication status	Published - 15 May 2023

Keywords

Ceramides/metabolism
Homeostasis
Humans
Mutation
Sphingolipids/genetics
Neurodevelopment
Genetics
Lipid rafts
Cell Biology

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10.1172/JCI165019Licence: CC BY

165019.2-20230508182711-covered-e0fd13ba177f913fd3156f593ead4cfdFinal published version, 9.13 MBLicence: CC BY

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Gehin, C., Lone, M. A., Lee, W., Capolupo, L., Ho, S., Adeyemi, A. M., Gerkes, E. H., Stegmann, A. P., López-Martín, E., Bermejo-Sánchez, E., Martínez-Delgado, B., Zweier, C., Kraus, C., Popp, B., Strehlow, V., Gräfe, D., Knerr, I., Jones, E. R., Zamuner, S., ... Gennarino, V. A. (2023). CERT1 mutations perturb human development by disrupting sphingolipid homeostasis. Journal of Clinical Investigation, 133(10), Article e165019. https://doi.org/10.1172/JCI165019

@article{333504e9b3d24f21828cf57fff1953c1,

title = "CERT1 mutations perturb human development by disrupting sphingolipid homeostasis",

abstract = "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.",

keywords = "Ceramides/metabolism, Homeostasis, Humans, Mutation, Sphingolipids/genetics, Neurodevelopment, Genetics, Lipid rafts, Cell Biology",

author = "Charlotte Gehin and Lone, {Museer A} and Winston Lee and Laura Capolupo and Sylvia Ho and Adeyemi, {Adekemi M} and Gerkes, {Erica H} and Stegmann, {Alexander Pa} and Estrella L{\'o}pez-Mart{\'i}n and Eva Bermejo-S{\'a}nchez and Beatriz Mart{\'i}nez-Delgado and Christiane Zweier and Cornelia Kraus and Bernt Popp and Vincent Strehlow and Daniel Gr{\"a}fe and Ina Knerr and Jones, {Eppie R} and Stefano Zamuner and Abriata, {Luciano A} and Vidya Kunnathully and Moeller, {Brandon E} and Anthony Vocat and Samuel Rommelaere and Jean-Philippe Bocquete and Evelyne Ruchti and Greta Limoni and {Van Campenhoudt}, Marine and Samuel Bourgeat and Petra Henklein and Christian Gilissen and {van Bon}, {Bregje W} and Rolph Pfundt and Willemsen, {Marjolein H} and Schieving, {Jolanda H} and Emanuela Leonardi and Fiorenza Soli and Alessandra Murgia and Hui Guo and Qiumeng Zhang and Kun Xia and Fagerberg, {Christina R} and Beier, {Christoph P} and Larsen, {Martin J} and Irene Valenzuela and Paula Fern{\'a}ndez-{\'A}lvarez and Shiyi Xiong and Robert {\'S}migiel and Vanesa L{\'o}pez-Gonz{\'a}lez and Llu{\'i}s Armengol and Manuela Morleo and Angelo Selicorni and Annalaura Torella and Moira Blyth and Cooper, {Nicola S} and Valerie Wilson and Renske Oegema and Yvan Herenger and Aurore Garde and Ange-Line Bruel and {Tran Mau-Them}, Frederic and Maddocks, {Alexis Br} and Bain, {Jennifer M} and Bhat, {Musadiq A} and Gregory Costain and Peter Kannu and Ashish Marwaha and Champaigne, {Neena L} and Friez, {Michael J} and Richardson, {Ellen B} and Gowda, {Vykuntaraju K} and Srinivasan, {Varunvenkat M} and Yask Gupta and Lim, {Tze Y} and Simone Sanna-Cherchi and Bruno Lemaitre and Toshiyuki Yamaji and Kentaro Hanada and Burke, {John E} and Jak{\v s}i{\'c}, {Ana Marija} and McCabe, {Brian D} and {De Los Rios}, Paolo and Thorsten Hornemann and Giovanni D'Angelo and Gennarino, {Vincenzo A}",

note = "Funding Information: This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R01NS109858, to VAG); the Paul A. Marks Scholar Program at the Columbia University Vagelos College of Physicians and Surgeons (to VAG); a TIGER grant from the TAUB Institute at the Columbia Vagelos College of Physicians and Scientists (to VAG); the Swiss National Science Foundation (SNF 31003A-179371, to TH); the European Joint Program on Rare Diseases (EJP RD+SNF 32ER30-187505, to TH); the Swiss Cancer League (KFS-4999-02-2020, to GD); the EPFL institutional fund (to GD); the Kristian Gerhard Jebsen Foundation (to GD); the Swiss National Science Foundation (SNSF) (310030_184926, to GD); the Swiss Foundation for Research on Muscle Disease (FSRMM, to MAL); the Natural Science and Engineering Research Council of Canada (Discovery Grant 2020-04241, to JEB); the Italian Ministry of Health Young Investigator Grant (GR-2011-02347754, to EL); the Fondazione Istituto di Ricerca Pediatrica – Citt{\`a} della Speranza (18-04, to EL); the Wroclaw Medical University (SUB.E160.21.004, to RS); the National Science Centre, Poland (2017/27/B/NZ5/0222, to RS); Telethon Undiagnosed Diseases Program (TUDP) (GSP15001); the Temple Street Foundation/Children{\textquoteright}s Health Foundation Ireland (RPAC 19-02, to IK); the Deutsche Forschungsgemeinschaft (DFG) (PO2366/2–1, to BP); the Instituto de Salud Carlos III, Spain (to ELM, EBS, and BMD); the National Natural Science Foundation of China (81871079 and 81730036, to HG and KX); and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (R01 DK115574, to SSC). Funding Information: The DEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. The funders were not involved in the study design, data acquisition, analysis, or writing of the manuscript. Funding for the DECIPHER project was provided by Wellcome. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. Publisher Copyright: {\textcopyright} 2023, Gehin et al.",

year = "2023",

month = may,

day = "15",

doi = "10.1172/JCI165019",

language = "English",

volume = "133",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "10",

}

Gehin, C, Lone, MA, Lee, W, Capolupo, L, Ho, S, Adeyemi, AM, Gerkes, EH, Stegmann, AP, López-Martín, E, Bermejo-Sánchez, E, Martínez-Delgado, B, Zweier, C, Kraus, C, Popp, B, Strehlow, V, Gräfe, D, Knerr, I, Jones, ER, Zamuner, S, Abriata, LA, Kunnathully, V, Moeller, BE, Vocat, A, Rommelaere, S, Bocquete, J-P, Ruchti, E, Limoni, G, Van Campenhoudt, M, Bourgeat, S, Henklein, P, Gilissen, C, van Bon, BW, Pfundt, R, Willemsen, MH, Schieving, JH, Leonardi, E, Soli, F, Murgia, A, Guo, H, Zhang, Q, Xia, K, Fagerberg, CR, Beier, CP, Larsen, MJ, Valenzuela, I, Fernández-Álvarez, P, Xiong, S, Śmigiel, R, López-González, V, Armengol, L, Morleo, M, Selicorni, A, Torella, A, Blyth, M, Cooper, NS, Wilson, V, Oegema, R, Herenger, Y, Garde, A, Bruel, A-L, Tran Mau-Them, F, Maddocks, AB, Bain, JM, Bhat, MA, Costain, G, Kannu, P, Marwaha, A, Champaigne, NL, Friez, MJ, Richardson, EB, Gowda, VK, Srinivasan, VM, Gupta, Y, Lim, TY, Sanna-Cherchi, S, Lemaitre, B, Yamaji, T, Hanada, K, Burke, JE, Jakšić, AM, McCabe, BD, De Los Rios, P, Hornemann, T, D'Angelo, G & Gennarino, VA 2023, 'CERT1 mutations perturb human development by disrupting sphingolipid homeostasis', Journal of Clinical Investigation, vol. 133, no. 10, e165019. https://doi.org/10.1172/JCI165019

TY - JOUR

T1 - CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

AU - Gehin, Charlotte

AU - Lone, Museer A

AU - Lee, Winston

AU - Capolupo, Laura

AU - Ho, Sylvia

AU - Adeyemi, Adekemi M

AU - Gerkes, Erica H

AU - Stegmann, Alexander Pa

AU - López-Martín, Estrella

AU - Bermejo-Sánchez, Eva

AU - Martínez-Delgado, Beatriz

AU - Zweier, Christiane

AU - Kraus, Cornelia

AU - Popp, Bernt

AU - Strehlow, Vincent

AU - Gräfe, Daniel

AU - Knerr, Ina

AU - Jones, Eppie R

AU - Zamuner, Stefano

AU - Abriata, Luciano A

AU - Kunnathully, Vidya

AU - Moeller, Brandon E

AU - Vocat, Anthony

AU - Rommelaere, Samuel

AU - Bocquete, Jean-Philippe

AU - Ruchti, Evelyne

AU - Limoni, Greta

AU - Van Campenhoudt, Marine

AU - Bourgeat, Samuel

AU - Henklein, Petra

AU - Gilissen, Christian

AU - van Bon, Bregje W

AU - Pfundt, Rolph

AU - Willemsen, Marjolein H

AU - Schieving, Jolanda H

AU - Leonardi, Emanuela

AU - Soli, Fiorenza

AU - Murgia, Alessandra

AU - Guo, Hui

AU - Zhang, Qiumeng

AU - Xia, Kun

AU - Fagerberg, Christina R

AU - Beier, Christoph P

AU - Larsen, Martin J

AU - Valenzuela, Irene

AU - Fernández-Álvarez, Paula

AU - Xiong, Shiyi

AU - Śmigiel, Robert

AU - López-González, Vanesa

AU - Armengol, Lluís

AU - Morleo, Manuela

AU - Selicorni, Angelo

AU - Torella, Annalaura

AU - Blyth, Moira

AU - Cooper, Nicola S

AU - Wilson, Valerie

AU - Oegema, Renske

AU - Herenger, Yvan

AU - Garde, Aurore

AU - Bruel, Ange-Line

AU - Tran Mau-Them, Frederic

AU - Maddocks, Alexis Br

AU - Bain, Jennifer M

AU - Bhat, Musadiq A

AU - Costain, Gregory

AU - Kannu, Peter

AU - Marwaha, Ashish

AU - Champaigne, Neena L

AU - Friez, Michael J

AU - Richardson, Ellen B

AU - Gowda, Vykuntaraju K

AU - Srinivasan, Varunvenkat M

AU - Gupta, Yask

AU - Lim, Tze Y

AU - Sanna-Cherchi, Simone

AU - Lemaitre, Bruno

AU - Yamaji, Toshiyuki

AU - Hanada, Kentaro

AU - Burke, John E

AU - Jakšić, Ana Marija

AU - McCabe, Brian D

AU - De Los Rios, Paolo

AU - Hornemann, Thorsten

AU - D'Angelo, Giovanni

AU - Gennarino, Vincenzo A

N1 - Funding Information: This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R01NS109858, to VAG); the Paul A. Marks Scholar Program at the Columbia University Vagelos College of Physicians and Surgeons (to VAG); a TIGER grant from the TAUB Institute at the Columbia Vagelos College of Physicians and Scientists (to VAG); the Swiss National Science Foundation (SNF 31003A-179371, to TH); the European Joint Program on Rare Diseases (EJP RD+SNF 32ER30-187505, to TH); the Swiss Cancer League (KFS-4999-02-2020, to GD); the EPFL institutional fund (to GD); the Kristian Gerhard Jebsen Foundation (to GD); the Swiss National Science Foundation (SNSF) (310030_184926, to GD); the Swiss Foundation for Research on Muscle Disease (FSRMM, to MAL); the Natural Science and Engineering Research Council of Canada (Discovery Grant 2020-04241, to JEB); the Italian Ministry of Health Young Investigator Grant (GR-2011-02347754, to EL); the Fondazione Istituto di Ricerca Pediatrica – Città della Speranza (18-04, to EL); the Wroclaw Medical University (SUB.E160.21.004, to RS); the National Science Centre, Poland (2017/27/B/NZ5/0222, to RS); Telethon Undiagnosed Diseases Program (TUDP) (GSP15001); the Temple Street Foundation/Children’s Health Foundation Ireland (RPAC 19-02, to IK); the Deutsche Forschungsgemeinschaft (DFG) (PO2366/2–1, to BP); the Instituto de Salud Carlos III, Spain (to ELM, EBS, and BMD); the National Natural Science Foundation of China (81871079 and 81730036, to HG and KX); and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (R01 DK115574, to SSC). Funding Information: The DEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. The funders were not involved in the study design, data acquisition, analysis, or writing of the manuscript. Funding for the DECIPHER project was provided by Wellcome. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. Publisher Copyright: © 2023, Gehin et al.

PY - 2023/5/15

Y1 - 2023/5/15

N2 - 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.

AB - 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.

KW - Ceramides/metabolism

KW - Homeostasis

KW - Humans

KW - Mutation

KW - Sphingolipids/genetics

KW - Neurodevelopment

KW - Genetics

KW - Lipid rafts

KW - Cell Biology

UR - http://www.scopus.com/inward/record.url?scp=85159733545&partnerID=8YFLogxK

U2 - 10.1172/JCI165019

DO - 10.1172/JCI165019

M3 - Article

C2 - 36976648

SN - 0021-9738

VL - 133

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 10

M1 - e165019

ER -

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

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