Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy

Abstract

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.

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Fig. 1: Autosomal recessive cone–rod dystrophy (CRD) or maculopathy families and associated TLCD3B variants.
Fig. 2: The clinical phenotype for each patient indicates degeneration of the central (macular) and outer retinal layers.
Fig. 3: The full-field electroretinographies (ffERGs) indicate generalized cone system dysfunction with rod photoreceptor involvement in some patients.
Fig. 4: Tlcd3b knockout mice exhibit retinal degeneration and significant loss of cone photoreceptors.

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Acknowledgements

First, we thank the patients and families who kindly participated in this study. This work was supported by grants from Fight for Sight (UK) (Early Career Investigator Award to G.A.), Moorfields Eye Charity, NIHR BioResource–Rare Disease Consortium, the NIHR BRC at Great Ormond Street Hospital for Child Health, and the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, UCL Institute of Ophthalmology and Cambridge University Hospitals, the Competitive Renewal Grant of Knights Templar Eye Foundation to J.W., and grants from the National Eye Institute (EY022356, EY018571, EY002520), Retinal Research Foundation, and National Institutes of Health (NIH) shared instrument grant S10OD023469 to R.C.

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Correspondence to Rui Chen PhD.

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Bertrand, R.E., Wang, J., Xiong, K.H. et al. Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy. Genet Med (2020). https://doi.org/10.1038/s41436-020-01003-x

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Key words

  • retinal degeneration
  • ceramide synthase
  • cone–rod degeneration
  • novel disease gene
  • TLCD3B

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