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Abstract: SA-PO782

The Pkhd1del3-67 Deletion Disrupts Local Genomic Architecture Resulting in Reduced Expression of Tfap-2b in the Developing Eye and Peters Anomaly

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Ishimoto, Yu, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Nakaya, Naoki, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Barbosa Sabanero, Karla Yadira, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Zhou, Fang, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Kerosuo, Laura, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Tomarev, Stanislav I., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Menezes, Luis F., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Germino, Gregory G., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
Background

Mutations in PKHD1, a gene that spans ~500kb, cause Autosomal Recessive Polycystic Kidney Disease (ARPKD). Mice with genomic deletion from intron 2 through the 3’UTR of Pkhd1 develop eye and teeth abnormalities. While neither phenotype has been associated with ARPKD, a transgenic mouse strain with a genomic rearrangement mapping close to the Pkhd1 locus and a strain with Tfap2b deletion in Neural Crest Cells (NCC) develop similar eye pathology.

Methods

We recorded eye weights and intraocular pressures (IOP) of Pkhd1del3-67/del3-67 mice and litter mate controls from P7 through P28 and performed histological evaluation of their eyes from E15.5 through P28. We generated Pkhd1del3-67/+;Tfap2b ko/+ transheterozygotes and evaluated their eye, kidney and liver phenotypes.

Results

All Pkhd1del3-67/del3-67 mice developed Peters anomaly, a form of anterior segment dysgenesis, with elevated IOP, corneal opacities and most having enlarged globes. Retinal ganglion cell (RGC) number was normal at P7 but decreased by P28. Adult eyes had disruption of the iridocorneal angle with the iris adherent to the cornea, a finding associated with angle closure glaucoma. E15.5 mouse eyes had less compact cornea with large gaps within stroma and cornea and lens adhesion. Pkhd1 expression was low in all cell types of normal E15.5 eyes. Tfap2b expression was normal in pre-migratory and migrating NCC of Pkhd1del3-67/del3-67 but decreased in corneal endothelium and angle tissue at E15.5, suggesting a defect in NCC-derived cells after they have already populated the eye cup. Pkhd1del3-67/+; Tfap2b ko/+ developed eye and incisor abnormalities like those of Pkhd1del3-67/del3-67 but had phenotypically normal livers and kidneys.

Conclusion

Our results suggest that the eye and incisor abnormalities observed in Pkhd1del3-67/del3-67 mice likely result from disruption of local genomic architecture compromising Tfap-2b expression in NCC-derived cells, rather than from loss of expression of Pkhd1. This model will be useful for studying the complexities of Tfap-2b gene regulation and interventions that prevent RGC loss in glaucoma. GWAS studies have identified SNPs in PKHD1 associated with elevated IOP. Our data may suggest a possible explanation for this relationship.

Funding

  • NIDDK Support