June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Ceramide synthase TLCD3B as a novel gene associated with human recessive cone-rod dystrophy and maculopathy
Author Affiliations & Notes
  • Rui Chen
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
  • Renae Elaine Bertrand
    Biochemistry and Molecular Biology, Baylor College of Medicine , Houston, Texas, United States
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
  • Jun Wang
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
  • Kaitlyn H. Xiong
    BioSciences, Rice University, Houston, Texas, United States
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
  • Chinthana Thangavel
    BioSciences, Rice University, Houston, Texas, United States
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
  • Xinye Qian
    Biochemistry and Molecular Biology, Baylor College of Medicine , Houston, Texas, United States
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
  • Rola Ba-Abbad
    Moorfields Eye Hospital, United Kingdom
    UCL Institute of Ophthalmology, United Kingdom
  • Renata Simoes
    Instituto de Ensino e Pesquisa, Brazil
  • Shirley Aparecida Madureira Sampaio
    INRET Clinica e Centro de Pesquisa, Brazil
  • Keren J. Carss
    Haematology, University of Cambridge, United Kingdom
    NIHR BioResource-Rare Diseases, Cambridge University Hospitals, United Kingdom
  • F. Lucy Raymond
    Haematology, University of Cambridge, United Kingdom
    Medical Genetics, Cambridge Institute for Medical Research, United Kingdom
  • Anthony G Robson
    Moorfields Eye Hospital, United Kingdom
    UCL Institute of Ophthalmology, United Kingdom
  • Yumei Li
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
  • Andrew R. Webster
    Moorfields Eye Hospital, United Kingdom
    UCL Institute of Ophthalmology, United Kingdom
  • Gavin Arno
    UCL Institute of Ophthalmology, United Kingdom
    Moorfields Eye Hospital, United Kingdom
  • Fernanda Belga Ottoni Porto
    INRET Clinica e Centro de Pesquisa, Brazil
  • Footnotes
    Commercial Relationships   Rui Chen, None; Renae Bertrand, None; Jun Wang, None; Kaitlyn Xiong, None; Chinthana Thangavel, None; Xinye Qian, None; Rola Ba-Abbad, None; Renata Simoes, None; Shirley Sampaio, None; Keren Carss, None; F. Raymond, None; Anthony Robson, None; Yumei Li, None; Andrew Webster, None; Gavin Arno, None; Fernanda Porto, None
  • Footnotes
    Support  NEI Grant EY022356, EY018571, Retina Research Foundation
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1953. doi:
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      Rui Chen, Renae Elaine Bertrand, Jun Wang, Kaitlyn H. Xiong, Chinthana Thangavel, Xinye Qian, Rola Ba-Abbad, Renata Simoes, Shirley Aparecida Madureira Sampaio, Keren J. Carss, F. Lucy Raymond, Anthony G Robson, Yumei Li, Andrew R. Webster, Gavin Arno, Fernanda Belga Ottoni Porto; Ceramide synthase TLCD3B as a novel gene associated with human recessive cone-rod dystrophy and maculopathy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1953.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Inherited retinal dystrophy (IRD) is a genetically heterogeneous group of diseases resulting in irreversible vision loss. Identification and functional studies to understand the underlying molecular causes of IRD are important for patient diagnosis and therapy development. Our study aims at identifying novel IRD associated genes through a combination of next generation sequencing and animal model studies.

Methods : Patients were recruited from the inherited retinal disorders clinic. Clinical data included best-corrected visual acuity, fundus autofluorescence, optical coherence tomography, and full-field electroretinography (ERG). Candidate variants in TLCD3B identified by NGS were investigated. RNA-sequencing data was obtained from dbGap for expression analysis of ceramide synthases. The retinal function in Tlcd3bKO/KO mice was assessed by ERG performed at 7-months. The murine retinal cross-sections were stained with Hematoxylin and eosin (H&E) and immunofluorescent staining was performed on retinal whole mounts to assess the cone photoreceptors.

Results : Novel homozygous mutations in TLCD3B were identified in four patients from three unrelated families diagnosed with cone-rod dystrophy (CRD) with or without maculopathy, providing the first link between TLCD3B and IRD. All patients presented with progressive central vision loss and macular atrophy. Full-field ERG abnormalities were either confined to photopic recordings or showed photopic and scotopic ERG involvement. The retinal function and morphology of Tlcd3bKO/KO mice showed reduced scotopic and photopic b-wave responses and a 20% reduction of the outer nuclear layer thickness. Immunofluorescent staining revealed a 30% reduction in cone photoreceptors in Tlcd3bKO/KO mice.

Conclusions : This study is the first to associate mutations in the ceramide gene TLCD3B with CRD and maculopathy in humans. The Tlcd3bKO/KO mice recapitulate the human peripheral retinal phenotype and can serve as a good model to study the mechanism of degeneration and develop targeted therapies. The Tlcd3b knock out model is the first in vivo model that demonstrates ceramide to be essential for the survival and function of photoreceptor cells.

This is a 2020 ARVO Annual Meeting abstract.

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