| RRC ID |
63230
|
| 著者 |
Murakami H, Tamura N, Enomoto Y, Shimasaki K, Kurosawa K, Hanada K.
|
| タイトル |
Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.
|
| ジャーナル |
PLoS One
|
| 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.
|
| 巻・号 |
15(12)
|
| ページ |
e0243980
|
| 公開日 |
2020-1-1
|
| DOI |
10.1371/journal.pone.0243980
|
| PII |
PONE-D-20-26020
|
| PMID |
33347465
|
| PMC |
PMC7751862
|
| MeSH |
Cells, Cultured
Female
Gain of Function Mutation*
HCT116 Cells
Humans
Intellectual Disability / genetics*
Intellectual Disability / pathology
Protein Domains
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / metabolism
Young Adult
|
| IF |
2.74
|
| リソース情報 |
| ヒト・動物細胞 |
HCT116(RCB2979) |
