Studies of mice with a large deletion of the ARPKD-associated Pkhd1 locus likely explain its GWAS association with glaucoma in humans.

PKHD1, the gene primarily mutated in human autosomal recessive polycystic kidney disease, is one of the top 20 genes associated with primary open angle glaucoma (POAG) and associated endophenotypes in Genome-Wide Association Studies. Here, we show that Pkhd1 del3-67/del3-67 mutant mice develop congenital glaucoma due to anterior segment dysgenesis. Using a combination of genetic, epigenetic, bioinformatics and mouse developmental biology approaches, we show that Pkhd1 del3-67/del3-67 mice lack Tfap2b and AP-2β expression in a subset of periocular mesenchymal cells at E13.5 and its derivatives. Our data suggest that the Pkhd1 del3-67 deletion disrupts features of the Pkhd1-Tfap2b genomic architecture essential for Tfap2b cell-specific activities. Consistent with this model, Pkhd1 del3-67/+ ;Tfap2b ko/+trans-heterozygotes lack Tfap2b and AP-2β in relevant cell-types and have similar eye abnormalities as neural crest cell-specific Tfap2b ko mutants. These findings provide a likely causal explanation for how SNPs associated with PKHD1 are functionally linked to POAG and add insight into understanding the complexity of disease-causing SNP associations and gene regulatory mechanisms.