Kidney Week

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

• Genetic Diseases: Cystic - Genetic Analysis and Extrarenal Manifestations
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

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

Yu Ishimoto,

• Nakaya, Naoki, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Naoki Nakaya,

• Barbosa Sabanero, Karla Yadira, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Karla Yadira Barbosa Sabanero,

• Zhou, Fang, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Fang Zhou,

• Kerosuo, Laura, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Laura Kerosuo,

• Tomarev, Stanislav I., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Stanislav I. Tomarev,

• Menezes, Luis F., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Luis F. Menezes,

• Germino, Gregory G., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Gregory G. Germino,

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 Pkhd1^{del3-67/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 Pkhd1^del3-67/+;Tfap2b ^ko/+ transheterozygotes and evaluated their eye, kidney and liver phenotypes.

Results

All Pkhd1^{del3-67/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 Pkhd1^{del3-67/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. Pkhd1^del3-67/+; Tfap2b ^ko/+ developed eye and incisor abnormalities like those of Pkhd1^{del3-67/del3-67} but had phenotypically normal livers and kidneys.

Conclusion

Our results suggest that the eye and incisor abnormalities observed in Pkhd1^{del3-67/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