CERT1 mutations perturb human development by disrupting sphingolipid homeostasis
Charlotte Gehin, et al.
Charlotte Gehin, et al.
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Research Article Cell biology Genetics

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.

Authors

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 Marija Jakšić, Brian D. McCabe, Paolo De Los Rios, Thorsten Hornemann, Giovanni D’Angelo, Vincenzo A. Gennarino

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Figure 1

Mutations in CERT1 lead to a neurodevelopmental syndrome.

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Mutations in CERT1 lead to a neurodevelopmental syndrome. (A) Schematic ...
(A) Schematic representation of functional domains in CERT. The N-terminal PH domain interacts with phosphoinositide phosphatidylinositol-4-phosphate [PtdIns(4)P] (25) on the trans Golgi. The SRR is the target of protein kinase D (PKD) and casein kinase 1γ2 (CSNK1G2) phosphorylation. The FFAT (2 phenylalanines in an acidic tract) motif interacts with the integral membrane proteins VAP-A and VAP-B on the ER (71), and a C-terminal START-related domain extracts Cer from the ER membrane and delivers it to the trans Golgi (7). The schematic shows coding variants in CERT1 (NP_005704) in our cohort of 31 individuals above the gene diagram and other individuals identified from clinical databases (DECIPHER, version 9.31, ClinVar, and VKGL) below it (Supplemental Table 1). Colors indicate the age of onset; gray indicates that no information is available. The distribution of gnomAD singleton missense variants for healthy individuals is plotted below. (B) Range of severity in motor delays compared with the 75th percentile (light gray) and 25th percentile (dark gray), adapted from values published by the Denver Developmental Screening Test II. White and black circles indicate delayed sitting and walking ages, respectively; asterisks indicate that the individual needs sitting or walking support. White circles with an arrow indicate individuals who are currently immobile or have not yet developed independent walking. (C) Heatmap shows the degree of intellectual disability (ID), speech delay (SD), and motor delay (MD) of the patients bearing frequent CERT1 mutations. See Supplemental Table 2 for scores. C1, cluster 1; C2, cluster 2; C3, cluster 3; C4, cluster 4.