Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy
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Updated: Dec 5, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Renae Elaine Bertrand1,2, Jun Wang2,3, Kaitlyn H Xiong2,4
1Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
Purpose:
Previous studies suggest that ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. However, no pathogenic variant in ceramide synthases has been identified in human patients and knockout of various ceramide synthases in mice has not led to photoreceptor degeneration.
Methods:
Exome sequencing was used to identify candidate disease genes in patients with vision loss as confirmed by standard evaluation methods, including electroretinography (ERG) and optical coherence tomography. The vision loss phenotype in mice was evaluated by ERG and histological analyses.
Results:
Here we have identified four patients with cone-rod dystrophy or maculopathy from three families carrying pathogenic variants in TLCD3B. Consistent with the phenotype observed in patients, the Tlcd3bKO/KO mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina.
Conclusion:
Our results provide a link between loss-of-function variants in a ceramide synthase gene and human retinal dystrophy. Establishment of the Tlcd3b knockout murine model, an in vivo photoreceptor cell degeneration model due to loss of a ceramide synthase, will provide a unique opportunity in probing the role of ceramide in survival and function of photoreceptor cells.
Insights
Pathogenic variants in the ceramide synthase gene TLCD3B cause retinal dystrophy in humans. A Tlcd3b knockout mouse model demonstrates photoreceptor degeneration, offering insights into ceramide
Area of Science:
- Ophthalmology
- Genetics
- Cell Biology
Background:
- Ceramides are implicated as proapoptotic lipids, potentially affecting neuronal cells like photoreceptors.
- Previous research has not identified pathogenic variants in ceramide synthases in human patients or photoreceptor degeneration in knockout mice.
Purpose of the Study:
- To identify genes responsible for vision loss in patients with retinal dystrophy.
- To investigate the role of ceramide synthases in photoreceptor survival and function.
Main Methods:
- Exome sequencing was employed to identify disease-causing genes in patients with vision loss.
- Phenotypic evaluation in patients included electroretinography (ERG) and optical coherence tomography.
- Vision loss in a Tlcd3b knockout mouse model was assessed using ERG and histological analyses.
Main Results:
- Pathogenic variants in TLCD3B were identified in four patients from three families with cone-rod dystrophy or maculopathy.
- Tlcd3b knockout mice exhibited reduced cone photoreceptor responses, outer nuclear layer thinning, and cone photoreceptor loss.
- These findings establish a link between ceramide synthase gene variants and human retinal dystrophy.
Conclusions:
- Loss-of-function variants in TLCD3B are associated with human retinal dystrophy.
- The Tlcd3b knockout mouse serves as a valuable model for studying ceramide's role in photoreceptor degeneration.
- This model facilitates further investigation into ceramide's function in photoreceptor cell survival and maintenance.
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