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

ABSTRACT 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.