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Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT

Intellectual disability (ID) is a developmental disorder that includes both intellectual and adaptive functioning deficits in conceptual, social, and practical domains. Although evidence-based interventions for patients have long been desired, their progress has been hindered due to various determin...

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Autores principales: Murakami, Hiroaki, Tamura, Norito, Enomoto, Yumi, Shimasaki, Kentaro, Kurosawa, Kenji, Hanada, Kentaro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751862/
https://www.ncbi.nlm.nih.gov/pubmed/33347465
http://dx.doi.org/10.1371/journal.pone.0243980
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author Murakami, Hiroaki
Tamura, Norito
Enomoto, Yumi
Shimasaki, Kentaro
Kurosawa, Kenji
Hanada, Kentaro
author_facet Murakami, Hiroaki
Tamura, Norito
Enomoto, Yumi
Shimasaki, Kentaro
Kurosawa, Kenji
Hanada, Kentaro
author_sort Murakami, Hiroaki
collection PubMed
description Intellectual disability (ID) is a developmental disorder that includes both intellectual and adaptive functioning deficits in conceptual, social, and practical domains. Although evidence-based interventions for patients have long been desired, their progress has been hindered due to various determinants. One of these determinants is the complexity of the origins of ID. The ceramide transport protein (CERT) encoded by CERT1 mediates inter-organelle trafficking of ceramide for the synthesis of intracellular sphingomyelin. Utilizing whole exome sequencing analysis, we identified a novel CERT variant, which substitutes a serine at position 135 (S135) for a proline in a patient with severe ID. Biochemical analysis showed that S135 is essential for hyperphosphorylation of a serine-repeat motif of CERT, which is required for down-regulation of CERT activity. Amino acid replacements of S135 abnormally activated CERT and induced an intracellular punctate distribution pattern of this protein. These results identified specific ID-associated CERT1 mutations that induced gain-of-function effects on CERT activity. These findings provide a possible molecular basis for not only new diagnostics but also a conceivable pharmaceutical intervention for ID disorders caused by gain-of-function mutations in CERT1.
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spelling pubmed-77518622021-01-05 Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT Murakami, Hiroaki Tamura, Norito Enomoto, Yumi Shimasaki, Kentaro Kurosawa, Kenji Hanada, Kentaro PLoS One Research Article Intellectual disability (ID) is a developmental disorder that includes both intellectual and adaptive functioning deficits in conceptual, social, and practical domains. Although evidence-based interventions for patients have long been desired, their progress has been hindered due to various determinants. One of these determinants is the complexity of the origins of ID. The ceramide transport protein (CERT) encoded by CERT1 mediates inter-organelle trafficking of ceramide for the synthesis of intracellular sphingomyelin. Utilizing whole exome sequencing analysis, we identified a novel CERT variant, which substitutes a serine at position 135 (S135) for a proline in a patient with severe ID. Biochemical analysis showed that S135 is essential for hyperphosphorylation of a serine-repeat motif of CERT, which is required for down-regulation of CERT activity. Amino acid replacements of S135 abnormally activated CERT and induced an intracellular punctate distribution pattern of this protein. These results identified specific ID-associated CERT1 mutations that induced gain-of-function effects on CERT activity. These findings provide a possible molecular basis for not only new diagnostics but also a conceivable pharmaceutical intervention for ID disorders caused by gain-of-function mutations in CERT1. Public Library of Science 2020-12-21 /pmc/articles/PMC7751862/ /pubmed/33347465 http://dx.doi.org/10.1371/journal.pone.0243980 Text en © 2020 Murakami et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Murakami, Hiroaki
Tamura, Norito
Enomoto, Yumi
Shimasaki, Kentaro
Kurosawa, Kenji
Hanada, Kentaro
Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT
title Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT
title_full Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT
title_fullStr Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT
title_full_unstemmed Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT
title_short Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT
title_sort intellectual disability-associated gain-of-function mutations in cert1 that encodes the ceramide transport protein cert
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751862/
https://www.ncbi.nlm.nih.gov/pubmed/33347465
http://dx.doi.org/10.1371/journal.pone.0243980
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