July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Microphthalmia, coloboma and WNT signalling
Author Affiliations & Notes
  • Steven Eamegdool
    Children's Medical Research Institute, Westmead, New South Wales, Australia
  • To Ha Loi
    Children's Medical Research Institute, Westmead, New South Wales, Australia
  • Anson Cheng
    Children's Medical Research Institute, Westmead, New South Wales, Australia
  • Robyn V Jamieson
    Children's Medical Research Institute, Westmead, New South Wales, Australia
  • Footnotes
    Commercial Relationships   Steven Eamegdool, None; To Ha Loi, None; Anson Cheng, None; Robyn Jamieson, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 5411. doi:
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      Steven Eamegdool, To Ha Loi, Anson Cheng, Robyn V Jamieson; Microphthalmia, coloboma and WNT signalling. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5411.

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

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Purpose : Microphthalmia and coloboma (M/C) are congenital eye abnormalities leading to small eyes associated with failure of closure of the optic fissure. Incomplete penetrance and variable expression are among the factors hampering the disease gene identification process. Here we employed whole exome sequencing (WES) for affected members of an autosomal dominant M/C family. We identified a novel pathogenic variant in the Frizzled 5 (FZD5) gene, which encodes a receptor involved in the WNT signalling pathway, suggesting a role in development of the M/C phenotype.

Methods : In this study, we performed WES on four affected individuals from two generations in an Australian family with autosomal dominant M/C, where mutations in known disease genes were not previously identified. The human FZD5 gene, harbouring either the FZD5-WT or FZD5-mutated version, was cloned into a GFP-expressing vector, and transfected into Caco-2 and HEK293 cells. Subsequently, we performed immunostaining to visualize cellular FZD5 expression. Expression of FZD5 in induced pluripotent stem cell-derived retinal organoids was also investigated, to model the role of FZD5 during development.

Results : Heterozygous variants shared by all four affected family members were selected for the analysis. Variants were filtered based on their population frequency, pathogenicity prediction and conservation scores. Subsequently we prioritised variants in previously investigated animal disease genes and pathways known to be involved in eye disease. The top candidate variant, a novel frameshift mutation, was in the FZD5 gene, which was confirmed by Sanger sequencing. Furthermore, FZD5-WT showed clear and even cell membrane localization in our cellular studies. The FZD5-mutated version showed weak and punctate localization around the cell membrane.

Conclusions : Our findings, based on a combined employment of exome-wide variant analysis, biological process gene ontology comparison, literature data and functional analyses, demonstrate the role of the FZD5 gene in eye morphogenesis and impact of its mutation on M/C pathogenesis.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.


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