Haploinsufficiency Does Not Cause Polycystic Kidney Disease or Polycystic Liver Disease in Mice.

BACKGROUND

Heterozygous mutations that can cause autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD) have been described previously, but their roles in ADPKD and PLD are largely unknown. With the increase in polycystic kidney disease caused by gene mutations in recent years, a suitable animal model is still needed to further explore the pathogenic role of this gene.

METHODS

To construct a mouse model of gene deletion, we analyzed gene structure and designed two CRISPR-/Cas9-based targeting strategies. The Cas9/sgRNA we constructed was microinjected into fertilized mouse eggs to obtain chimeric F0 mice. Mice with stable genotypes were selected from offspring born after mating F0 mice with wild-type mice.

RESULTS

We found that homozygous mutation of the gene in C57BL/6 mice resulted in early embryonic lethality, and there were no cysts in the kidneys or livers of mice. Additionally, protein expression was reduced by at least 50%, while the expression of ADPKD proteins (PC1 and PC2) and acetylated tubulin was not affected in the kidney. However, the mice did not show any abnormal clinical phenotypes after birth and failed to reveal renal tubule dilatation or any abnormalities of the glomeruli in the kidney.

CONCLUSIONS

Homozygous mutations are lethal in the fetal stage, and haploinsufficiency does not cause kidney or liver cysts in mice, suggesting that it may not be the causative gene in polycystic kidney disease.