June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Revealing Candidate Inherited Retinal Disorder Genes through Genome-wide Screening of Knockout Mice
Author Affiliations & Notes
  • Andy Shao
    University of Nevada Reno, Reno, Nevada, United States
  • Dave Clary
    UC Davis Mouse Biology Program, California, United States
  • KC Kent Lloyd
    UC Davis Mouse Biology Program, California, United States
  • Ala Moshiri
    Ophthalmology, University of California Davis School of Medicine, Sacramento, California, United States
  • Footnotes
    Commercial Relationships   Andy Shao, None; Dave Clary, None; KC Kent Lloyd, None; Ala Moshiri, None
  • Footnotes
    Support  NONE
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2591. doi:
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    • Get Citation

      Andy Shao, Dave Clary, KC Kent Lloyd, Ala Moshiri; Revealing Candidate Inherited Retinal Disorder Genes through Genome-wide Screening of Knockout Mice. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2591.

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

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Abstract

Purpose : Identify candidate inherited retinal disorder (IRD) genes through International Mouse Phenotyping Consortium (IMPC) generated single gene knockout mouse strains with retinal abnormalities, with particular interest in Usher Syndrome and heritable retinal vascular disorders such as Familial Exudative Vitreoretinopathy (FEVR).

Methods : The IMPC database currently contains phenotypic data for approximately 7,000 mice with targeted single gene knockouts. We investigated all strains with abnormal retinal phenotypes and further enriched our search for strains with concomitant hearing or retinal vascular abnormalities. Candidate genes were then analyzed for potential protein-protein interactions via bioinformatic analysis with STRING and PANTHER proteomics databases and cross-referenced against established IRD-causative genes as presented by the RETNET database.

Results : Initial interrogation revealed 182 knockout strains with retinal abnormalities, 153 of which have not been associated with retinal pathology to date. Of these 182 knockout strains, 15 had concomitant impaired auditory function, none of which have been implicated with Usher syndrome to date. Furthermore, 108 strains had vascular phenotypes, 106 of which were novel for retinal vascular anomalies based on search of literature. Bioinformatic analysis revealed two clusters of predicted protein-protein interactions between the 108 candidate vascular disorder genes from IMPC mice and established angiogenesis/vascular pathology genes. These clusters presented 13 candidate genes for retinal vascular disorders, 12 of which have not been implicated in retinal disorders. Analysis of gene clusters revealed evidence for involvement of Wnt/Notch/PDGFR/Rac1 signaling pathways.

Conclusions : We present 153 targeted gene deletions previously unknown to cause retinal pathology. Fifteen of these 153 are candidate Usher Syndrome genes. Thirteen of these 153 are candidates for heritable retinal vascular disorders such as FEVR. These genes are of interest not only for improving screening of human IRD patients, but also for elucidating novel biological mechanisms involved in retinal development.

This is a 2021 ARVO Annual Meeting abstract.

 

Examples of fundus photography in various knockout strains generated by the IMPC. These fundus photos demonstrate pigmentary and vascular changes suggestive of retinal degeneration. Wild type C57BL/6N mouse fundus is shown on the left for comparison

Examples of fundus photography in various knockout strains generated by the IMPC. These fundus photos demonstrate pigmentary and vascular changes suggestive of retinal degeneration. Wild type C57BL/6N mouse fundus is shown on the left for comparison

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