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Intellectual-disability-associated mutations in the ceramide transport protein gene CERT1 lead to aberrant function and subcellular distribution

The lipid molecule ceramide is transported from the endoplasmic reticulum to the Golgi apparatus for sphingomyelin production via the ceramide transport protein (CERT), encoded by CERT1. Hyperphosphorylation of CERT’s serine-repeat motif (SRM) decreases its functionality. Some forms of inherited int...

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Autores principales: Tamura, Norito, Sakai, Shota, Martorell, Loreto, Colomé, Roser, Mizuike, Aya, Goto, Asako, Ortigoza-Escobar, Juan Darío, Hanada, Kentaro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605338/
https://www.ncbi.nlm.nih.gov/pubmed/34688657
http://dx.doi.org/10.1016/j.jbc.2021.101338
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author Tamura, Norito
Sakai, Shota
Martorell, Loreto
Colomé, Roser
Mizuike, Aya
Goto, Asako
Ortigoza-Escobar, Juan Darío
Hanada, Kentaro
author_facet Tamura, Norito
Sakai, Shota
Martorell, Loreto
Colomé, Roser
Mizuike, Aya
Goto, Asako
Ortigoza-Escobar, Juan Darío
Hanada, Kentaro
author_sort Tamura, Norito
collection PubMed
description The lipid molecule ceramide is transported from the endoplasmic reticulum to the Golgi apparatus for sphingomyelin production via the ceramide transport protein (CERT), encoded by CERT1. Hyperphosphorylation of CERT’s serine-repeat motif (SRM) decreases its functionality. Some forms of inherited intellectual disability (ID) have been associated with a serine-to-leucine substitution in the SRM (S132L mutation) and a glycine-to-arginine substitution outside the SRM (G243R mutation) in CERT; however, it is unclear if mutations outside the SRM disrupt the control of CERT functionality. In the current investigation, we identified a new CERT1 variant (dupAA) in a patient with mild ID that resulted from a frameshift at the C-terminus of CERT1. However, familial analysis revealed that the dupAA variant was not associated with ID, allowing us to utilize it as a disease-matched negative control for CERT1 variants that are associated with ID. Biochemical analysis showed that G243R and S132L, but not dupAA, impair SRM hyperphosphorylation and render the CERT variants excessively active. Additionally, both S132L and G243R mutations but not dupAA caused the proteins to be distributed in a punctate subcellular manner. On the basis of these findings, we infer that the majority of ID-associated CERT variants may impair SRM phosphorylation-dependent repression, resulting in an increase in sphingomyelin production concurrent with CERT subcellular redistribution.
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spelling pubmed-86053382021-11-24 Intellectual-disability-associated mutations in the ceramide transport protein gene CERT1 lead to aberrant function and subcellular distribution Tamura, Norito Sakai, Shota Martorell, Loreto Colomé, Roser Mizuike, Aya Goto, Asako Ortigoza-Escobar, Juan Darío Hanada, Kentaro J Biol Chem Research Article The lipid molecule ceramide is transported from the endoplasmic reticulum to the Golgi apparatus for sphingomyelin production via the ceramide transport protein (CERT), encoded by CERT1. Hyperphosphorylation of CERT’s serine-repeat motif (SRM) decreases its functionality. Some forms of inherited intellectual disability (ID) have been associated with a serine-to-leucine substitution in the SRM (S132L mutation) and a glycine-to-arginine substitution outside the SRM (G243R mutation) in CERT; however, it is unclear if mutations outside the SRM disrupt the control of CERT functionality. In the current investigation, we identified a new CERT1 variant (dupAA) in a patient with mild ID that resulted from a frameshift at the C-terminus of CERT1. However, familial analysis revealed that the dupAA variant was not associated with ID, allowing us to utilize it as a disease-matched negative control for CERT1 variants that are associated with ID. Biochemical analysis showed that G243R and S132L, but not dupAA, impair SRM hyperphosphorylation and render the CERT variants excessively active. Additionally, both S132L and G243R mutations but not dupAA caused the proteins to be distributed in a punctate subcellular manner. On the basis of these findings, we infer that the majority of ID-associated CERT variants may impair SRM phosphorylation-dependent repression, resulting in an increase in sphingomyelin production concurrent with CERT subcellular redistribution. American Society for Biochemistry and Molecular Biology 2021-10-22 /pmc/articles/PMC8605338/ /pubmed/34688657 http://dx.doi.org/10.1016/j.jbc.2021.101338 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Tamura, Norito
Sakai, Shota
Martorell, Loreto
Colomé, Roser
Mizuike, Aya
Goto, Asako
Ortigoza-Escobar, Juan Darío
Hanada, Kentaro
Intellectual-disability-associated mutations in the ceramide transport protein gene CERT1 lead to aberrant function and subcellular distribution
title Intellectual-disability-associated mutations in the ceramide transport protein gene CERT1 lead to aberrant function and subcellular distribution
title_full Intellectual-disability-associated mutations in the ceramide transport protein gene CERT1 lead to aberrant function and subcellular distribution
title_fullStr Intellectual-disability-associated mutations in the ceramide transport protein gene CERT1 lead to aberrant function and subcellular distribution
title_full_unstemmed Intellectual-disability-associated mutations in the ceramide transport protein gene CERT1 lead to aberrant function and subcellular distribution
title_short Intellectual-disability-associated mutations in the ceramide transport protein gene CERT1 lead to aberrant function and subcellular distribution
title_sort intellectual-disability-associated mutations in the ceramide transport protein gene cert1 lead to aberrant function and subcellular distribution
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605338/
https://www.ncbi.nlm.nih.gov/pubmed/34688657
http://dx.doi.org/10.1016/j.jbc.2021.101338
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