In:
PLOS ONE, Public Library of Science (PLoS), Vol. 15, No. 12 ( 2020-12-21), p. e0243980-
Abstract:
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 .
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0243980
DOI:
10.1371/journal.pone.0243980.g001
DOI:
10.1371/journal.pone.0243980.g002
DOI:
10.1371/journal.pone.0243980.g003
DOI:
10.1371/journal.pone.0243980.g004
DOI:
10.1371/journal.pone.0243980.g005
DOI:
10.1371/journal.pone.0243980.t001
DOI:
10.1371/journal.pone.0243980.s001
DOI:
10.1371/journal.pone.0243980.s002
DOI:
10.1371/journal.pone.0243980.s003
DOI:
10.1371/journal.pone.0243980.s004
DOI:
10.1371/journal.pone.0243980.s005
DOI:
10.1371/journal.pone.0243980.s006
DOI:
10.1371/journal.pone.0243980.s007
DOI:
10.1371/journal.pone.0243980.r001
DOI:
10.1371/journal.pone.0243980.r002
DOI:
10.1371/journal.pone.0243980.r003
DOI:
10.1371/journal.pone.0243980.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2267670-3
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