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 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

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 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. 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 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^*

^*Corresponding author voor dit werk

Onderzoeksoutput: Article › Academic › peer review

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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.

Originele taal-2	English
Artikelnummer	e165019
Aantal pagina's	17
Tijdschrift	Journal of Clinical Investigation
Volume	133
Nummer van het tijdschrift	10
DOI's	https://doi.org/10.1172/JCI165019
Status	Published - 15-mei-2023

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CERT1 mutations perturb human development by disrupting sphingolipid homeostasisFinal publisher's version, 9,13 MBLicentie: 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. A., 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), Artikel e165019. https://doi.org/10.1172/JCI165019

@article{760d0d3ebdb24161b5b3ac56b17b9731,

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.",

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 P.A.} 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 Bocquete, {Jean Philippe} 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 Bruel, {Ange Line} and Mau-Them, {Frederic Tran} and Maddocks, {Alexis B.R.} 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 Marjia} and McCabe, {Brian D.} and {De Los Rios}, Paolo and Thorsten Hornemann and Giovanni D{\textquoteright}Angelo and Gennarino, {Vincenzo A.}",

note = "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 = "AMER SOC CLINICAL INVESTIGATION INC",

number = "10",

}

Gehin, C, Lone, MA, Lee, W, Capolupo, L, Ho, S, Adeyemi, AM, Gerkes, EH, Stegmann, APA, 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, JP, 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, AL, Mau-Them, FT, Maddocks, ABR, 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, nr. 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 P.A.

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 - Mau-Them, Frederic Tran

AU - Maddocks, Alexis B.R.

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 Marjia

AU - McCabe, Brian D.

AU - De Los Rios, Paolo

AU - Hornemann, Thorsten

AU - D’Angelo, Giovanni

AU - Gennarino, Vincenzo A.

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.

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

U2 - 10.1172/JCI165019

DO - 10.1172/JCI165019

M3 - Article

C2 - 36976648

AN - SCOPUS:85159733545

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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