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Kidney Week

Abstract: SA-OR24

CU062, the Product of the C21orf62 Gene, Is a Polycystin-1 Ligand

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Ward, Christopher J., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Kleene, Steven J., University of Cincinnati, Cincinnati, Ohio, United States
  • Calvet, James P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Lea, Wendy A., University of Kansas Medical Center, Kansas City, Kansas, United States
Background


The PKD1 gene, encoding the protein polycystin-1 (PC1), is responsible for 85% of cases of mutation positive autosomal dominant polycystic kidney disease (ADPKD) and is the most common genetic cause of renal failure (1:800). PC1 has been shown to be present on easily accessible urinary exosome-like vesicles (ELVs) and to be decreased in individuals with PKD1 mutations. Label-free mass spectrometry comparison of ELVs from normal and PKD1 urine showed that several other proteins were decreased to a degree similar to PC1, including a small signal peptide bearing protein of unknown function, CU062, the product of the C21orf62 gene.

Methods


To determine whether this novel protein is involved in cystogenesis, we applied a genetic approach and deleted the entire C21orf62 open reading frame in c57Black6/J mice. We also investigated the ability of CU062 to interact with the entire 4302 aa ORF of PC1 and mapped the interacting domains. Furthermore, we probed its ability to gate the PC1/PC2 channel using primary cilium patch clamp.

Results


A TALEN induced deletion of the entire C21orf62 ORF generated mice that were grossly phenotypically normal, and both sexes were fertile. Close inspection of the kidney showed that about 25% of the homozygous null animals had mild tubular dilation in the loop of Henle and collecting duct. The C21orf62del allele exacerbated the Pkd1R3277C phenotype as assessed by kidney weight/body weight ratio, ANOVA interaction p=0.0017. In vitro binding studies indicated that CU062 interacts with PKD domains 2-17 and most tightly with domains 15-17 in an SDS stable manner. We subsequently showed that extracellular application of pure CU062 activated polycystin-2 (PC2) dependent currents in primary cilia of mIMCD-3 cells. CU062 was shown to be expressed most prominently in the vasa recta (VR) and the endothelium of large blood vessels but not in kidney tubules.

Conclusion


These data suggest that CU062 might be a circulating ligand for PC1 and may be filtered through the glomerulus to interact with PC1 on exosomes. CU062 accounts for a subset of PC1 functions as its genetic deletion leads to a milder phenotype than that observed in Pkd1 homozygous null mice.


Funding

  • NIDDK Support