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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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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. |
format | Online Article Text |
id | pubmed-7751862 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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