2. Academic Validation
  3. Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy

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

  • Genet Med. 2021 Mar;23(3):488-497. doi: 10.1038/s41436-020-01003-x.
Renae Elaine Bertrand 1 2,  Jun Wang 2 3,  Kaitlyn H Xiong 2 4,  Chinthana Thangavel 2 4,  Xinye Qian 1 2,  Rola Ba-Abbad 5,  Qingnan Liang 1 2,  Renata T Simões 6,  Shirley A M Sampaio 7,  Keren J Carss 8 9,  F Lucy Raymond 8 10,  Anthony G Robson 11,  Andrew R Webster 5 11,  Gavin Arno 5 11 12,  Fernanda Belga Ottoni Porto 7,  Rui Chen 13 14
Affiliations

Affiliations

  • 1 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 2 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 4 Department of BioSciences, Rice University, Houston, TX, USA.
  • 5 Moorfields Eye Hospital, London, UK.
  • 6 Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte (IEP/SCBH), Belo Horizonte, Minas Gerais, Brazil.
  • 7 INRET Clínica e Centro de Pesquisa, Belo Horizonte, Minas Gerais, Brazil.
  • 8 Department of Haematology, University of Cambridge, Cambridge, UK.
  • 9 NIHR BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, UK.
  • 10 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
  • 11 UCL Institute of Ophthalmology, London, UK.
  • 12 Great Ormond Street Hospital for Children, London, UK.
  • 13 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 14 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. [email protected].
PMID: 33077892 DOI: 10.1038/s41436-020-01003-x
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.

Keywords

TLCD3B; ceramide synthase; cone–rod degeneration; novel disease gene; retinal degeneration.

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