Related Experiment Video
Updated: Aug 5, 2025
13:36
Author Spotlight: Dendritic Cells Maturation Using Sialidases-Based Enzymatic Treatment of the Cell Surface
Published on: October 20, 2023
3.6K
CERT1 mutations perturb human development by disrupting sphingolipid homeostasis
Charlotte Gehin1, Museer A Lone2, Winston Lee3,4
1Institute of Bioengineering (IBI), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
The Journal of Clinical Investigation
|March 28, 2023
Summary
Mutations in the ceramide transporter CERT1 cause intellectual disability by disrupting sphingolipid regulation. Inhibiting CERT1 shows promise for treating ceramide transporter (CerTra) syndrome.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Sphingolipids are crucial for neural functions like synaptic transmission.
- Mutations in the ceramide transporter CERT1 are linked to intellectual disability, but the mechanism is unclear.
Purpose of the Study:
- To investigate the pathogenic mechanism of de novo missense variants in CERT1.
- To understand the role of CERT1 autoregulation in sphingolipid homeostasis and its connection to clinical severity.
Main Methods:
- Characterization of 31 individuals with de novo CERT1 missense variants.
- Structural analysis of a novel dimeric helical domain in CERT1.
- Pharmacological inhibition of CERT1 in a Drosophila melanogaster model.
Main Results:
- Several CERT1 variants disrupt a dimeric helical domain essential for homeostatic inactivation.
- Disruption of CERT1 autoregulation leads to uncontrolled sphingolipid production.
- Pharmacological inhibition of CERT1 ameliorated disease phenotypes in a Drosophila model.
Conclusions:
- CERT1 autoregulation is central to controlling sphingolipid biosynthetic flux.
- Findings reveal insights into CERT1 structural organization and its role in CerTra syndrome.
- Pharmacological targeting of CERT1 offers a potential therapeutic strategy for CerTra syndrome.
Related Concept Videos
03:14Notch Signaling Pathway
4.3K
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
4.3K
02:18Alternative RNA Splicing
21.5K
Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
21.5K
01:33Pleiotropy
40.7K
Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
40.7K
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
2.2K
Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
2.2K
01:39Mutations
83.9K
Overview
83.9K
01:22Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal
2.3K
Erythropoietin-producing hepatocellular carcinoma receptor (Eph) and its ligand, Eph receptor-interacting protein (Ephrin) were first discovered in the human carcinoma cell line, hence the name. Ephrin-Eph interaction guides cells to reach their appropriate location in adult tissues. They also play an essential role in the immune system by helping in immune cell migration, adhesion, and activation. Based on their structure and function, Eph is divided into two classes — EphA and EphB.
2.3K