June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Hypomorphic mutations in CLUAP1 cause Leber congenital amaurosis
Author Affiliations & Notes
  • Zachry Soens
    Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
  • Yuanyuan Li
    Genetics, Yale University School of Medicine, New Haven, CT
  • Li Zhao
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
    Structural and Computational Biology & Molecular Biophysics, Baylor College of Medicine, Houston, TX
  • Yumei Li
    Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
  • Zhaoxia Sun
    Genetics, Yale University School of Medicine, New Haven, CT
  • Ayesha Khan
    McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, QC, Canada
  • Norma Fajardo
    McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, QC, Canada
  • Irma Lopez
    McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, QC, Canada
  • Robert K Koenekoop
    McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, QC, Canada
  • Rui Chen
    Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
  • Footnotes
    Commercial Relationships Zachry Soens, None; Yuanyuan Li, None; Li Zhao, None; Yumei Li, None; Zhaoxia Sun, None; Ayesha Khan, None; Norma Fajardo, None; Irma Lopez, None; Robert Koenekoop, None; Rui Chen, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 4349. doi:
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      Zachry Soens, Yuanyuan Li, Li Zhao, Yumei Li, Zhaoxia Sun, Ayesha Khan, Norma Fajardo, Irma Lopez, Robert K Koenekoop, Rui Chen, ; Hypomorphic mutations in CLUAP1 cause Leber congenital amaurosis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4349.

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

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Abstract
 
Purpose
 

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal disease affecting ~1/50,000 newborns and manifests as severe visual impairment or blindness within the first few months of life. Currently ~20 genes have been associated with LCA however the genetic basis of approximately 25% of LCA patients remains unknown. This represents one of the main translational challenges in LCA research as understanding the genetic basis of a patient’s disease is necessary for personalized medicine and genetic counseling. The purpose of this study was to fill the knowledge gap by identifying novel LCA disease genes.

 
Methods
 

Whole exome sequencing was performed on an LCA patient cohort consisting of 212 probands previously screened for mutations in all currently known retina disease genes. A next generation sequencing analysis pipeline developed in-house was used to process data to identify novel candidate disease genes. Zebrafish were used as an animal model system to confirm the pathogenicity of putative mutations.

 
Results
 

One of the novel candidate LCA disease genes identified in this study was CLUAP1. CLUAP1 is a gene required for ciliogenesis and cilia maintenance. CLUAP1 knockout mice and zebrafish exhibit embryonic lethality due to cilia related defects. CLUAP1 knockout zebrafish have absent photoreceptor outer segments by five days post fertilization and the number of cell nuclei in the outer nuclear layer is severely diminished. Rescue experiments in the zebrafish model revealed that identified mutations are hypomorphic.

 
Conclusions
 

Consistent with the idea that CLUAP1 plays an important role in cilia function, our results suggest that strong hypomorphic mutations can result in dysfunctional photoreceptors without systemic abnormalities. This represents the first report of CLUAP1 as a human disease gene and a new LCA gene.  

 
cluap1-/- zebrafish embryos were injected with increasing concentrations of cluap1 mRNA in order to rescue the cluap1-/- phenotype. The rescue ability compared to controls of wildtype cluap1 mRNA is plotted with cluap1 mRNA harboring an LCA proband's mutation. Mutant Cluap1 is observed to be strongly hypomorphic.
 
cluap1-/- zebrafish embryos were injected with increasing concentrations of cluap1 mRNA in order to rescue the cluap1-/- phenotype. The rescue ability compared to controls of wildtype cluap1 mRNA is plotted with cluap1 mRNA harboring an LCA proband's mutation. Mutant Cluap1 is observed to be strongly hypomorphic.

 
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