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

Abstract

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 Pkhd1del3-67/del3-67 mice also exhibit CG and ASD. Integrating genetic, epigenetic, bioinformatic and developmental analyses, we show that Pkhd1del3-67/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 Pkhd1del3-67 deletion disrupts features of the Pkhd1-Tfap2b genomic architecture essential for Tfap2b cell-specific function. Consistent with this model, Pkhd1del3-67/+;Tfap2bko/+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. Genetic studies have linked the PKHD1–TFAP2B locus to glaucoma risk, but the underlying mechanism is unclear. Here, the authors show that deleting Pkhd1 in mice disrupts Tfap2b regulation in developing eye tissues, causing congenital glaucoma-like defects and implicating TFAP2B dysregulation in disease risk.