| First Author | Ishimoto Y | Year | 2026 |
| Journal | Nat Commun | Volume | 17 |
| Issue | 1 | PubMed ID | 42618573 |
| Mgi Jnum | J:391384 | Mgi Id | MGI:8403845 |
| Doi | 10.1038/s41467-026-75698-y | Citation | Ishimoto Y, et al. (2026) Deletion of ARPKD-associated Pkhd1 gene in mice results in decreased Tfap2b expression and eye abnormalities. Nat Commun 17(1) |
| abstractText | 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-2beta 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-2beta 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. |
