Deletion of ARPKD-associated Pkhd1 gene in mice results in decreased Tfap2b expression and eye abnormalities

Genome-wide association studies report single nucleotide polymorphisms (SNPs) in the PKHD1-TFAP2B genomic interval are associated with primary open-angle glaucoma (POAG) but do not distinguish the causal gene. While neural crest cell (NCC)-specific Tfap2b inactivation causes anterior segment dysgenesis (ASD) and congenital glaucoma (CG), PKHD1 mutations cause autosomal recessive polycystic kidney disease. We now show that Pkhd1^{del3-67/del3-67} mice also exhibit CG and ASD. Integrating genetic, epigenetic, bioinformatic and developmental analyses, 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 the Pkhd1^del3-67 deletion disrupts features of the Pkhd1-Tfap2b genomic architecture essential for Tfap2b cell-specific function. Consistent with this model, Pkhd1^del3-67/+;Tfap2b^ko/+mice develop ASD and lack Tfap2b and AP-2β in relevant cell-types. Our results suggest POAG-associated SNPs at this complex locus may impact disease risk by altering TFAP2B regulatory landscapes, providing a mechanistic link and highlighting regulatory complexity of disease-associated regions.