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



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.


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.


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.


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.


  1. 1.

    Ellingford JM, Barton S, Bhaskar S, et al. Molecular findings form 537 individuals with inherited retinal disease. J Med Genet. 2016;53:761–767.

    CAS  Article  Google Scholar 

  2. 2.

    Gill JS, Georgiou M, Kalitzeos A, et al. Progressive cone and cone–rod dystrophies: clinical features, molecular genetics and prospects for therapy. Br J Ophthalmol. 2019;103:711–720.

    Article  Google Scholar 

  3. 3.

    Eagle RC. Mechanisms of maculopathy. Ophthalmology. 1984;91:613–625.

    Article  Google Scholar 

  4. 4.

    Hannun Y, Obeid L. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008;9:139–150.

    CAS  Article  Google Scholar 

  5. 5.

    Kitatani K, Idkowiak-Baldys J, Hannun YA. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal. 2008;20:1010–1018.

    CAS  Article  Google Scholar 

  6. 6.

    Ferlazzo E, Italiano D, An I, et al. Description of a family with novel progressive myoclonus epilepsy and cognitive impairment. Mov Disord. 2009;24:1016–1022.

    Article  Google Scholar 

  7. 7.

    Laviad EL, Albee L, Pankova-Kholmyansky I, et al. Characterization of ceramide synthase 2 tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J Biol Chem. 2008;283:5677–5684.

    CAS  Article  Google Scholar 

  8. 8.

    Mizutani Y, Kihara A, Igarashi Y. Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J. 2005;390:263–271.

    CAS  Article  Google Scholar 

  9. 9.

    Riebeling C, Allegood JC, Wang E, et al. Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty Acyl-CoA donors. J Biol Chem. 2003;278:43452–43459.

    CAS  Article  Google Scholar 

  10. 10.

    Zhao L, Spassieva S, Jucius T, et al. A deficiency of ceramide biosynthesis causes cerebellar Purkinje cell neurodegeneration and lipofuscin accumulation. PLoS Genet. 2011;7:e1002063.

    CAS  Article  Google Scholar 

  11. 11.

    German O, Miranda G, Abrahan C, et al. Ceramide is a mediator of apoptosis in retina photoreceptors. Invest Ophthalmol Vis Sci. 2006;47:1658–1668.

    Article  Google Scholar 

  12. 12.

    Prado Spalm F, Vera M, Dibo M, et al. Ceramide induces the death of retina photoreceptors through activation of parthanatos. Mol Neurobiol. 2018;56:4760–4777.

    Article  Google Scholar 

  13. 13.

    Sanvicens N, Cotter T. Ceramide is the key mediator of oxidative stress-induced apoptosis in retinal photoreceptor cells. J Neurochem. 2006;98:1432–1444.

    CAS  Article  Google Scholar 

  14. 14.

    Ranty M, Carpentier S, Cournot M, et al. Ceramide production associated with retinal apoptosis after retinal detachment. Graefe’s Arch Clin Exp Ophthalmol. 2009;247:215–224.

    CAS  Article  Google Scholar 

  15. 15.

    Strettoi E, Gargini C, Novelli E, et al. Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa. Proc Natl Acad Sci U S A. 2010;107:18706–18711.

    CAS  Article  Google Scholar 

  16. 16.

    Eckl K, Tidhar R, Thiele H, et al. Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length. J Invest Dermatol. 2013;133:2202–2211.

  17. 17.

    Vanni N, Fruscione F, Ferlazzo E, et al. Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy. Ann Neurol. 2014;76:206–212.

    CAS  Article  Google Scholar 

  18. 18.

    Brüggen B, Kremser C, Bickert A, et al. Defective ceramide synthases in mice cause reduced amplitudes in electroretinograms and altered sphingolipied composition in retina and cornea. Eur J Neurosci. 2016;44:1700–1713.

    Article  Google Scholar 

  19. 19.

    Avela K, Sankila EM, Seitsonen S, et al. A founder mutation in CERKL is a major cause of retinal dystrophy in Finland. Acta Ophthalmol. 2018;96:183–191.

    CAS  Article  Google Scholar 

  20. 20.

    Fathinajafabadi A, Perez-Jimenez E, Riera M, et al. CERKL, a retinal disease gene, encodes an mRNA-binding protein that localizes in compact and untranslated mRNPs associated with microtubules. PLoS One. 2014;9:e87898.

    Article  Google Scholar 

  21. 21.

    Hu X, Lu Z, Yu S, et al. CERKL regulates autophagy via the NAD-dependent deacetylase SIRT1. Autophagy. 2019;15:453–465.

    CAS  Article  Google Scholar 

  22. 22.

    Yamashita-Sugahara Y, Tokuzawa Y, Nakachi Y, et al. Fam57b (family with sequence similarity 57, member B), a novel peroxisome proliferator-activated receptor γ target gene that regulates adipogenesis through ceramide synthesis. J Biol Chem. 2012;288:4522–4537.

    Article  Google Scholar 

  23. 23.

    Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–1760.

    CAS  Article  Google Scholar 

  24. 24.

    Wang F, Wang H, Tuan HF, et al. Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. Hum Genet. 2014;133:331–345.

    CAS  Article  Google Scholar 

  25. 25.

    Carss KJ, Arno G, Erwood M, et al. Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am J Hum Genet. 2017;100:75–90.

    CAS  Article  Google Scholar 

  26. 26.

    Wang J, Zhao L, Wang X, et al. GRIPT: a novel case-control analysis method for Mendelian disease gene discovery. Genome Biol. 2018;19:203.

    CAS  Article  Google Scholar 

  27. 27.

    Baba K, Piano I, Lyuboslavsky P, et al. Removal of clock gene Bmal1 from the retina affects retinal development and accelerates cone photoreceptor degeneration during aging. Proc Natl Acad Sci U S A. 2018;115:13099–104.

    CAS  Article  Google Scholar 

  28. 28.

    Blanks JC, Johnson LV. Specific binding of peanut lectin to a class of retinal photoreceptor cells. A species comparison. Invest Ophthalmol Vis Sci. 1984;25:546–557.

    CAS  PubMed  Google Scholar 

  29. 29.

    Ortín-Martínez A, Nadal-Nicolás FM, Jiménez-López M, et al. Number and distribution of mouse retinal cone photoreceptors: differences between an albino (Swiss) and a pigmented (C57/BL6) strain. PLoS One. 2014;9:1–12.

    Google Scholar 

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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