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 Lopez-Martin; Eva Bermejo-Sanchez; Beatriz Martinez-Delgado; Christiane Zweier; Cornelia Kraus; Bernt Popp; Vincent Strehlow; Daniel Graefe; 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 Fernandez-alvarez; Shiyi Xiong; Robert Smigiel; Vanesa Lopez-Gonzalez; Lluis Armengol; 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 Lopez-Martin, Eva Bermejo-Sanchez, Beatriz Martinez-Delgado, Christiane Zweier, Cornelia Kraus, Bernt Popp, Vincent Strehlow, Daniel Graefe, 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 Fernandez-alvarez, Shiyi Xiong, Robert Smigiel, Vanesa Lopez-Gonzalez, Lluis Armengol, Thorsten Hornemann^*, Giovanni D'Angelo^*, Vincenzo A. Gennarino^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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
Number of pages	17
Journal	Journal of Clinical Investigation
Volume	133
Issue number	10
DOIs	https://doi.org/10.1172/JCI165019
Publication status	Published - 15 May 2023

Keywords

TRANSPORT PROTEIN CERT
ENDOPLASMIC-RETICULUM
NONVESICULAR TRAFFICKING
SPHINGOMYELIN SYNTHASE
CERAMIDE TRAFFICKING
MASS-SPECTROMETRY
STRUCTURAL BASIS
GOLGI-APPARATUS
START DOMAINS
ASSOCIATION

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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., Lopez-Martin, E., Bermejo-Sanchez, E., Martinez-Delgado, B., Zweier, C., Kraus, C., Popp, B., Strehlow, V., Graefe, 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{a4531628dbda4240970087fb133d0cbc,

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 = "TRANSPORT PROTEIN CERT, ENDOPLASMIC-RETICULUM, NONVESICULAR TRAFFICKING, SPHINGOMYELIN SYNTHASE, CERAMIDE TRAFFICKING, MASS-SPECTROMETRY, STRUCTURAL BASIS, GOLGI-APPARATUS, START DOMAINS, ASSOCIATION",

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 Lopez-Martin and Eva Bermejo-Sanchez and Beatriz Martinez-Delgado and Christiane Zweier and Cornelia Kraus and Bernt Popp and Vincent Strehlow and Daniel Graefe 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 Bon, {Bregje W. van} 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 Fernandez-alvarez and Shiyi Xiong and Robert Smigiel and Vanesa Lopez-Gonzalez and Lluis Armengol and Thorsten Hornemann and Giovanni D'Angelo and Gennarino, {Vincenzo A.}",

year = "2023",

month = may,

day = "15",

doi = "10.1172/JCI165019",

language = "English",

volume = "133",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "10",

}

Gehin, C, Lone, MA, Lee, W, Capolupo, L, Ho, S, Adeyemi, AM, Gerkes, EH, Stegmann, APA, Lopez-Martin, E, Bermejo-Sanchez, E, Martinez-Delgado, B, Zweier, C, Kraus, C, Popp, B, Strehlow, V, Graefe, 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, Bon, BWV, 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, Fernandez-alvarez, P, Xiong, S, Smigiel, R, Lopez-Gonzalez, V, Armengol, L, 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 P. A.

AU - Lopez-Martin, Estrella

AU - Bermejo-Sanchez, Eva

AU - Martinez-Delgado, Beatriz

AU - Zweier, Christiane

AU - Kraus, Cornelia

AU - Popp, Bernt

AU - Strehlow, Vincent

AU - Graefe, 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 - Bon, Bregje W. van

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 - Fernandez-alvarez, Paula

AU - Xiong, Shiyi

AU - Smigiel, Robert

AU - Lopez-Gonzalez, Vanesa

AU - Armengol, Lluis

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.

KW - TRANSPORT PROTEIN CERT

KW - ENDOPLASMIC-RETICULUM

KW - NONVESICULAR TRAFFICKING

KW - SPHINGOMYELIN SYNTHASE

KW - CERAMIDE TRAFFICKING

KW - MASS-SPECTROMETRY

KW - STRUCTURAL BASIS

KW - GOLGI-APPARATUS

KW - START DOMAINS

KW - ASSOCIATION

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

Abstract

Keywords

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