Identification of Candidate Ciliopathy Genes Relevant to Childhood Blindness Syndromes by Genome-wide Screening of Knockout Mice

Abstract

Purpose : We aimed to identify candidate Mendelian ciliopathy genes relevant to childhood blindness syndromes by enriching all single gene homozygote or heterozygote knockout mouse strains produced by the International Mouse Phenotyping Consortium (IMPC) with abnormal ocular phenotypes with multiple abnormal phenotypes commonly found in human ciliopathy syndromes.

Methods : We enriched the set of knocked out genes with abnormal ocular phenotypes with the genes of knockout strains with concomitant abnormalities in renal function, renal morphology, reproductive tract function, and reproductive tract morphology. The resulting set of enriched genes were then analyzed for predicted protein-protein interactions with known cilia proteins resulting in a list of “candidate ciliopathy genes”. We then assessed these genes for novel association with disease by systematic literature review. From this analysis, thirty-two ciliopathy candidates were predicted to interact with known ciliopathy genes, either directly or through a secondary intermediate protein.

Results : Seven of the 32 genes have been previously identified as ciliopathy genes in non-human vertebrates, and one of these has been shown to function in human cilia. Therefore, we identified 31 novel human ciliopathy genes and 25 novel vertebrate genes with predicted roles in ciliary pathobiology. Representative histological and morphological evidence of phenotypes consistent with ciliopathies are presented from several of these ciliopathy candidates; Abi2, Wdr62, Ap4e1, Dync1li1, and Prkab1.

Conclusions : Here we present targeted deletions of 32 candidate ciliopathy genes identified by phenotyping of knockout mice, predictive bioinformatic analysis, and systematic literature review. These putative ciliopathy genes may be responsible for human syndromes including childhood blindness. Furthermore, these knockout strains are available to serve as models to test novel pre-clinical preventative or therapeutic strategies.

This is a 2021 ARVO Annual Meeting abstract.

 

Venn diagram showing intersection of IMPC genes associated with various phenotype subgroups, those highlighted in green outline have ocular and one or more other concomitant phenotype and are subsequently considered “Potential ciliopathy genes” STRING interaction map of known ciliopathy genes with potential ciliopathy genes.