Abstract: TH-PO599

Anks6-/- Mice Have Laterality Defects and Develop Renal Cystic Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Airik, Rannar, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Airik, Merlin, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Herdman, Nathan Allen, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Nephronophthisis-related ciliopathies (NPHP-RC) are a group of heterogeneous recessive kidney diseases, that are frequently associated with extra-renal organ malformations. Recently mutations in the ankyrin repeat and sterile alpha motif domain containing 6 (ANKS6) gene were identified, as causing nephronophthisis with extrarenal manifestations in humans (1). Anks6 localizes to the inversin compartment (INVS, NEK8, NPHP3) in the primary cilium, where it regulates the activity of NEK8 kinase (2). In order to study the function of Anks6 in mouse we generated an Anks6 transgenic mouse model.

Methods

Targeted Anks6 ES cells were obtained from KOMP and injected into blastocysts to generate the Anks6-/- mice. Loss of Anks6 expression in the mutant animals was confirmed by immunoblotting. Anks6 tissue expression in the kidneys was studied using X-gal staining and in situ hybridization. Gross morphological characterization and tissue histological analysis of the mutant mice was performed at E15.5, E18.5 and P0.

Results

Inactivation of Anks6 causes perinatal lethality in mice due to multiorgan abnormalities. Homozygous Anks6 mutant mice displayed situs inversus, with morphogenesis defects of the heart, lungs, liver and kidneys. Histological and molecular analysis of the kidneys revealed a defect in nephrogenesis that we localized to the glomerulus and proximal tubles in the mutant animals. In kidneys the mutant mice developed glomerular cystic disease.

Conclusion

Our data demonstrate that abrogation of Anks6 in mice leads to laterality and developmental defects in multiple organs, which resemble the phenotypes of mouse models for other inversin compartment components. Homozygous mutant mice recapitulate the major features of loss of ANKS6 function in humans, including liver fibrosis, cystic kidney disease and situs inversus. Together, Anks6-/- mouse represents a novel genetic model of NPHP-RC.

Funding

  • NIDDK Support