|Title||Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Bertrand, RElaine, Wang, J, Xiong, KH, Thangavel, C, Qian, X, Ba-Abbad, R, Liang, Q, Simões, RT, Sampaio, SAM, Carss, KJ, F Raymond, L, Robson, AG, Webster, AR, Arno, G, Porto, FBelga Otto, Chen, R|
|Date Published||2021 03|
|Keywords||Animals, Electroretinography, Humans, Mice, Oxidoreductases, Retina, Retinal Cone Photoreceptor Cells, Retinal Degeneration, Retinal Dystrophies|
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 Tlcd3b 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.
|Alternate Journal||Genet Med|
|PubMed Central ID||PMC7936949|
|Grant List||1S10RR026550 / NH / NIH HHS / United States |
S10 OD023469 / OD / NIH HHS / United States
R01 EY022356 / EY / NEI NIH HHS / United States
P30 EY002520 / EY / NEI NIH HHS / United States
R01 EY018571 / EY / NEI NIH HHS / United States
/ DH_ / Department of Health / United Kingdom