RRC ID 68558
Author Tamura N, Sakai S, Martorell L, Colomé R, Mizuike A, Goto A, Ortigoza-Escobar JD, Hanada K.
Title Intellectual-disability-associated mutations in the ceramide transport protein gene CERT1 lead to aberrant function and subcellular distribution.
Journal J Biol Chem
Abstract 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 frame-shift 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.
Volume 297(5)
Pages 101338
Published 2021-11-1
DOI 10.1016/j.jbc.2021.101338
PII S0021-9258(21)01144-3
PMID 34688657
PMC PMC8605338
MeSH Amino Acid Substitution Humans Intellectual Disability / enzymology* Intellectual Disability / genetics Mutation, Missense* Phosphorylation Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism* Protein Transport* Sphingomyelins / biosynthesis* Sphingomyelins / genetics
IF 4.238
Human and Animal Cells HCT116(RCB2979)